Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6]1.C(O)(=[O:23])C>O>[CH:6]([N:5]1[C:13]2[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:2][CH2:3][CH2:4]1)=[O:23]
Reactant: NCCn1cc(-c2ccccc2)c2cc(Cl)ccc21
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=CN1CCN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a suspension of 2.7 g. of 1-(2'-aminoethyl)-3-phenyl-5-chloro-indole hydrochloride in 30 ml. of acetic acid is added a solution of 2.7 g. of chromic anhydride in 3 ml. of water at 10°-15° C. The reaction mixture is stirred for 16 hours at 20° C. The reaction mixture is poured into 500 ml. of water and neutralized to pH 7-8 with ammonia water and extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. The solvent is removed by distillation to an oily residue, to which is added ethanol and insoluble matter is removed by filtration. The filtrate is evaporated to a solidal residue, to which is added isopropanol. After heating, the mixture is cooled to give a light brown insoluble substance, which is removed by filtration. Water is added to the filtrat, and the mixture is extracted with 300 ml. of ether, and ethereal layer was washed with water, dried and thereafter the ether is removed by distillation to give a light yellow-white powder. It is recrystallized from a solvent mixture of ethanol and hexane to give 1-formyl-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine having a melting point of 245° C. (decomp.). And, the crystals are colored around 230° C.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[O-].[Na+].C(O[CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19])C>C(O)C>[NH2:21][C:20]1[N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[N:9]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: CCOCC(C#N)C#N
Reactant: NNC1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnn(C2CCCCC2)c1N
Temperature: 70 °C
Yield: 66.2 %

Procedure:
To cyclohexylhydrazine hydrochloride (7.52 g, 50 mmol) generated above in 500 mL absolute ethanol was added sodium methoxide (Aldrich, 2.7 g, 50 mmol). The mixture was stirred briefly and ethoxymethylmalononitrile (Acros, 6.11 g, 50 mmol) was added in small portions over twenty minutes. The reaction mixture was then heated at 70° C. under argon overnight. On cooling, the reaction was concentrated and subjected to flash chromatography on silica gel (1:1 hexane:ethyl acetate) affording 6.3 g (66%) of a light brown solid. Compound 8: mp 99-103° C.; MS (ES+ calculated: 190.25; found: 191.15 M+H). HPLC (97% purity, retention time 11.135 minutes—Method A); 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 6.49 (br s, 2H), 4.02 (m, 1H), 1.80-1.10 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=2)=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CCOCC1
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2cccc(Cl)c2)ccc1OCCN1CCOCC1
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A solution of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (0.040 g, 0.12 mmol) in CH2Cl2 (1 mL) was treated with 3-chlorophenyl isocyanate (0.015 mL, 0.125 mmol). The reaction was stirred overnight, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown solid (0.016 g, 27%). LCMS m/z (%)=490 (M+H35Cl35Cl, 100), 492 (M+H35Cl37Cl, 76), 494 (M+H37Cl37Cl, 15). 1H NMR (400 MHz, DMSO-d6) δ: 8.92 (s, 1H), 8.79 (s, 1H), 7.74 (t, J=2.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.57 (dd, J=2.7, 6.3 Hz, 1H), 7.41 (d, J=2.7 Hz, 1H), 7.36-7.28 (m, 2H), 7.21 (d, J=9.0 Hz, 1H), 7.04 (dt, J=1.9, 7.4 Hz, 1H), 4.22-4.15 (m, 1H), 4.11-4.05 (m, 1H), 3.70 (s, 3H), 3.56-3.51 (m, 4H), 2.66-2.48 (m, 2H), 2.42-2.30 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH:18]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]O)([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH:18]([CH3:20])[CH3:19])[CH:23]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: CC(C)Oc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(OC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 3-isopropyloxybenzyl alcohol (118 mg, 0.710 mmol) were dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (165 mg, 0.629 mmol) and a diethyl azodicarboxylate toluene solution (2.2 M, 290 μL, 0.640 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 4 hours.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH2:18]Br)[CH:9]=1.Cl>CN(C=O)C>[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH2:18][O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[CH:9]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: OCC(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1COCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Nail (0.5 g of 60% dispersion in oil) in DMF (10 ml) was added trifluoroethanol (0.92 ml) and the mixture stirred for 30 minutes. After this time the mixture was cooled to 0° C. and a solution of methyl 4-bromo-2-bromomethylbenzoate (3.52 g) in DMF was added, and the resultant mixture stirred at room temperature for 1 hour. 0.5M HCl was added and the mixture extracted with ether. The organic extract was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to yield methyl 4-bromo-2-trifluoroethoxymethylbenzoate (3.89 g) as a yellow oil, NMR (CDCl3) 3.9(s,3H), 4.0(q,2H), 5.1(s,2H), 7.5(dd,1H), 7.85(d,1H), 7.9(s,1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[C:29]([Si:31]([CH3:34])([CH3:33])[CH3:32])#[CH:30].O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:32][Si:31]([C:29]#[C:30][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1)([CH3:34])[CH3:33]
Reactant: C#C[Si](C)(C)C
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)cnc43)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)C#Cc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a stirred suspension of (1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (152 mg, 0.30 mmol) from Step 2 of this Example in DMF (3 mL) were added CuI (6 mg, 0.032 mmol) and PdCl2(PPh3)2 (11 mg, 0.015 mmol). The mixture was purged with argon while ethynyltrimethylsilane (85 μL, 0.60 mmol) and TEA (127 μL, 0.90 mmol) were added sequentially. The resulting mixture was stirred at rt for 1 h. LCMS analysis showed that the reaction was complete. Water (30 mL) was added and the resulting dark brown solid was collected by filtration and dried to give crude (1R,2R)-2-((6-((6-((trimethylsilyl)ethynyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 70%). LCMS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]#[C:5][NH:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH2:3]C1.[C:14]1(C)C=CC=CC=1>[Cl-].[Na+].O>[CH:4]1([C:5]2[NH:6][C:7]3[C:8]([CH:14]=2)=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[CH2:1][CH2:3]1
Reactant: Fc1ccc(NC#CC2CC2)cc1
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc2[nH]c(C3CC3)cc2c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 2-cyclopropylethynyl-4-fluoro-phenylamine (0.80 g, 4.5 mmol) in PhMe (16 mL) is treated with InBr3 (80 mg, 0.23 mmol) and stirred at 110° C. for 0.5 h. The mixture is then poured over brine (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-25% EtOAc in heptane to afford 2-cyclopropyl-5-fluoro-1H-indole (610 mg, 78%). MS: 176 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.88 (s, NH, 1H), 7.12 (m, 2H), 6.83 (m, 1H), 6.09 (s, 1H), 1.90 (m, 1H), 0.95 (m, 2H), 0.77 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=1)=O.[CH2:25]1[C:30](=[O:31])[O:29][CH2:28][C:26]1=O>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:3]2[C:4]([C:6]3[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=3)=[C:25]3[C:30](=[O:31])[O:29][CH2:28][C:26]3=[N:1][C:2]=2[CH:20]=1
Reactant: COc1cc(N)c(C(=O)c2cc(OC)c(O)c(OC)c2)cc1OC
Reactant: O=C1COC(=O)C1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cc2nc3c(c(-c4cc(OC)c(O)c(OC)c4)c2cc1OC)C(=O)OC3
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
One drop of conc. sulfuric acid was added to a mixture of 2-amino-4,5,3',5'-tetramethoxy-4'-hydroxybenzophenone (0.333 g), tetronic acid (tetrahydrofuran-2,4-dione) (0.11 g) and acetic acid (10 ml), and the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residual oil was poured into water, neutralized with an aqueous saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 6,7-dimethoxy-9-(4-hydroxy-3,5-dimethoxyphenyl)furo[3,4-b]quinoline -1(3H)-one (0.349 g, 88%) which was then recrystallized from methanol. Pale yellow needles. mp. 247°-248° C.
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][OH:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[Li]CCCC.[CH2:18]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[C:24]1=[O:33])[CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1>[OH:32][C:25]1([C:2]2[C:3]([CH2:11][OH:12])=[CH:4][C:5]3[O:9][CH2:8][O:7][C:6]=3[CH:10]=2)[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:24]1=[O:33]
Reactant: OCc1cc2c(cc1Br)OCO2
Reactant: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2CO)OCO3)c2ccccc21
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 17.1 %

Procedure:
To a solution of (6-bromo-1,3-benzodioxol-5-yl)methanol (Mann, J., et al, J. Chem. Soc. Perkin Trans. 1 (1984):2081-8) (1.27 g, 5.50 mmol) in THF (45.0 mL) was added n-BuLi (5.00 mL, 2.0 M, 10.0 mmol) dropwise at −75° C. The reaction mixture was stirred at −75° C. for 45 min followed by the addition of a solution of 1-pentyl-1H-indole-2,3-dione (1.00 g, 4.60 mmol) in THF (20.0 mL) at −75° C. The resulting mixture was stirred at ambient temperature for 12 hrs and quenched with ammonium chloride solution (5.00 mL). More ethyl acetate and water were added and separated. The organic layer was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with 50% EtOAc:Hexanes to yield the title compound (0.29 g, 25%) as a solid: 1H NMR (300 MHz, CDCl3) δ 7.38-7.24 (m, 2H), 7.11 (t, 1H), 6.91 (d, 1H), 6.81 (s, 1H), 6.43 (s, 1H), 5.90-5.87 (m, 2H), 4.77 (dd, 2H), 3.75-3.56 (m, 2H), 1.75-1.58 (m, 2H), 1.26-1.35 (m, 2H), 0.89-0.83 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 177.8, 147.4, 147.2, 142.8, 133.5, 132.2, 131.1, 130.1, 125.3, 123.8, 111.4, 109.2, 108.1, 101.5, 79.5, 64.7, 40.4, 29.0, 26.8, 22.3, 13.9; MS (ES+) m/z 352.1 (M−17).
Reaction SMILES: [O:1]([CH2:9][CH2:10][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:12](=[O:23])[NH:13][C@@H:14]([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:1][CH2:9][CH2:10][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:12](=[O:23])[NH:13][C@@H:14]([CH3:22])[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16]
Reactant: COCCN(CCO[Si](C)(C)C(C)(C)C)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COCCN(CCO)C(=O)N[C@@H](C)C(=O)OC(C)(C)C

Procedure:
t-Butyl (2S)-2-[3-[2-(t-butyldimethylsiloxy)ethyl]-3-(2-methoxyethyl)ureido]propionate (Compound No. 3-1, 2.79 g) is dissolved in anhydrous tetrahydrofuran (11 ml) under a nitrogen atmosphere. Tetra-n-butylammonium fluoride (7.3 ml) is added to the solution at room temperature with stirring, and the mixture is stirred for one hour. Water is added to the reaction mixture, and the whole is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 2.14 g (quantitatively) of the titled compound (Compound No. 4-1).
Reaction SMILES: S(O)(O)(=O)=O.[OH:6][NH2:7].[CH3:8][O:9][CH2:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15].[OH-].[Na+]>O>[CH3:8][O:9][CH2:10][C:11]([C:12]1[CH:13]=[C:14]([NH2:15])[O:6][N:7]=1)([CH3:18])[CH3:17]
Reactant: COCC(C)(C)C(=O)CC#N
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC(C)(C)c1cc(N)on1
Temperature: 100 °C

Procedure:
Hydroxyamine sulfate (1.56 g, 9.504 mmol) is added to a stirred solution of 5-methoxy-4,4-dimethyl-3-oxo-pentanenitrile (2.95 g, 19.008 mmol) and sodium hydroxide (1.635 g, 40.865 mmol) in water (40 mL). The reaction mixture is heated in 100° C. oil bath for 6 hours. After this time, the reaction mixture is diluted with water and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 171 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>COCCOC>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH:18]([CH3:20])[CH3:19])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)nc(C)c1Br
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cc(OC(C)C)nc(C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
KTB (222 mg) was added to a suspension of 5-bromo-4,6-dimethylpyridin-2-ol obtained in Preparation Example 23(1) (400 mg) in DME (2 mL), and the mixture was stirred at room temperature for 30 minutes. Potassium carbonate (192 mg) and 2-iodopropane (572 mg) were added to the reaction mixture. The mixture was heated under reflux overnight. The reaction mixture was cooled to mom temperature, and the insoluble matter was removed by filtration and washed with DME. The filtrate was concentrated under reduced pressure. Chloroform was added to the residue. The solution was washed with a 0.1 N aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 50%) to give the title compound (133.9 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].I[CH2:18][CH3:19].[H-].[Li+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][CH3:19])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cc(-c2ccccc2)n[nH]1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccccc2)nn1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a 0° C. mixture of the above-prepared 5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (350 mg, 1.62 mmoles) and iodoethane (260 μL, 3.23 mmoles) in DMF (3 mL) was added neat LiH (spatula tip, excess) under a nitrogen atmosphere. The resulting mixture was warmed up to room temperature and stirred overnight. The crude reaction was cooled to 0° C., quenched with aqueous NH4Cl, diluted with ethyl acetate and enough water to dissolve all solids. The phases were separated, and the organic phase was washed sequentially with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The regioisomeric products separated and purified by flash chromatography (silica gel, hexanes/ethyl acetate gradient) to give the title compound (167 mg, 42% yield, higher Rf in hexanes/ethyl acetate) and the undesired regioisomer (175 mg, 44% yield) as white solids. 1H NMR (CDCl3, 400 MHz): 7.81 (d, 2H); 7.40 (dd, 2H); 7.29 (dd, 1H); 7.13 (s, 1H); 4.63 (q, 2H); 4.37 (q, 2H); 1.47 (t, 3H); 1.41 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[O:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)#[N:2].CS(C)=[O:20].[OH-].[Na+].OO>C(O)C.O>[NH2:2][C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)=[O:20]
Reactant: CS(C)=O
Reactant: COC(=O)c1ccc(C#N)c(OC2CCC2)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(C(=O)O)cc1OC1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of methyl 4-cyano-3-(cyclobutyloxy)benzoate (0.051 g, 0.23 mmol) in 2 ml of ethanol was added 0.5 ml of DMSO, 1 ml of 1N aqueous sodium hydroxide, 1 ml of 30% aqueous hydrogen peroxide, and the reaction mixture was stirred at RT for 18 hrs. The reaction mixture was diluted with 10 ml of water and the aqueous solution extracted three times with ethyl acetate (20 ml). The aqueous layer was acidified to pH 3-4 by portion-wise addition of aqueous hydrochloric acid, then extracted with ethyl acetate (3×20 mL). The organic solution was rotary evaporated to dryness and dried in vacuo to provide 4-(aminocarbonyl)-3-(cyclobutyloxy)benzoic acid (0.026 g, 50%). 1H NMR (400 MHz, DMSO-d6): 13.25 (s, 1H), 7.80 (d, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.55 (d, 1H), 7.41 (s, 1H), 4.88-4.85 (m, 1H), 2.44-2.43 (m, 2H), 2.18-2.14 (m, 2H), 1.99-1.73 (m, 2H). MS (EI) for C12H13NO4: 236 (MH+).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:6][C:7]([CH:10]=O)([CH3:9])[CH3:8].N1CCCC1>CO>[C:7]([C:10]1[C:2](=[CH2:3])[CH:1]=[CH:5][CH:4]=1)([CH3:9])([CH3:8])[CH3:6]
Reactant: CC(C)(C)C=O
Reactant: C1=CCC=C1
Solvent: C1CCNC1
Solvent: CO
Product: C=C1C=CC=C1C(C)(C)C

Procedure:
6,-tert-butyl-fulvene was prepared analogously by reaction of cyclopentadiene (31.7 g, 480 mmole), pivaldehyde (19.825 g, 230 mmol), and pyrrolidine (25 ml, 300 mmole) in methanol (250 ml). The yellow oil is kugel-rohr distilled at 70° C. and <1 torr yielding a bright yellow oil; 20.5 g (66.4%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[O:10][CH:11]=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[C:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](F)=[CH:17][CH:16]=1)#[N:14]>>[C:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[CH:11][O:10][C:6]2=3)=[CH:17][CH:16]=1)#[N:14]
Reactant: CCN1Cc2ccoc2C(O)C1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: CCN1Cc2ccoc2C(Oc2ccc(C#N)c3ccccc23)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 34) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-cyano-1-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C([N:8]([CH2:31][C@H:32]([OH:53])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41]CC2C=CC=CC=2)=[C:37]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:36]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:30]=[CH:29][C:18]([C:19]([NH:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[OH:53][C@H:32]([CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:36]=1)[CH2:31][NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:30]=[CH:29][C:18]([C:19]([NH:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)NNc4ccccc4)cc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(C(=O)NNc4ccccc4)cc3)CC2)ccc1O
Reaction time: 48 h

Procedure:
A mixture or 0.166 g of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]-N′-phenylbenzohydrazide (0.226 mmol) and of 0.1 g of 10% palladium-on-charcoal (50% in water) in a mixture of ethanol (3.9 ml) and tetrahydrofuran (2.93 ml) is placed under hydrogen atmosphere and stirred for 48 h. The catalyst is subsequently filtered off and the solvents are evaporated under reduced pressure. The title compound is obtained in the form of a white solid (0.02 g, 16%) after purification on silica gel (eluent: dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradient in 30 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: Fc1cc(I)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
To 5-chloro-2-fluoro-4-iodopyridine (600 mg, 2.331 mmol) was added DMSO (2.2 ml), trans-4-aminocyclohexanol (1074 mg, 9.32 mmol) and TEA (0.390 ml, 2.80 mmol). The resulting reaction mixture was stirred at 75° C. for 24 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (1×), water (1×), saturated salt solution (1×), dried over sodium sulfate, filtered and concentrated to yield a crude material. The crude material was purified by silica gel chromatography using a 40 g column eluting from 15%-75% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 750 mg of the title compound as free base, which was used in the next step without further purification. LCMS (m/z): 353.0 (MH+), retention time=0.56 min.