Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:14]>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13](=[O:14])[NH2:3])=[CH:17][CH:18]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(OC(N)=O)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 256.4 %

Procedure:
Diethylaniline (0.33 μL, 2.1 μmol, 1.1 equiv) and 4-methoxyphenyl chloroformate (0.85 μL, 5.7 μmol, 3.0 equiv) were added separately, each in one portion, to a stirred solution of the amine (1.0 mg, 1.9 μmol, 1 equiv) in dichloromethane (0.15 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred at 0° C. for 40 min, then was quenched by the addition of a 1:1 mixture of water and saturated aqueous sodium hydrogen carbonate solution (3 mL). The mixture was extracted with ethyl acetate (2×10 mL) and the combined organic layer was washed with a 1:1 mixture of brine solution and saturated aqueous sodium hydrogen carbonate solution (5 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to leave a colorless oil. Purification by flash column chromatography (50%→70% ethyl acetate-hexanes) gave the carbamic acid 4-methoxyphenyl ester derivative (0.9 mg, 70%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.Cl.[NH2:27][C@@H:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([Br:38])[CH:32]=1)[CH2:29][OH:30].C(Cl)CCl.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:27][C@@H:28]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([Br:38])[CH:32]=3)[CH2:29][OH:30])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: N[C@H](CO)c1cc(F)cc(Br)c1
Reactant: Nc1ncc([C@@H]2CC[C@@H](O)[C@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Nc1ncc([C@@H]2CC[C@@H](O)[C@H](F)C2)nc1-c1ccc(C(=O)N[C@H](CO)c2cc(F)cc(Br)c2)c(F)c1
Reaction time: 15 h
Yield: 40.4 %

Procedure:
To a solution of 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (20 mg, 0.057 mmol) in DMF (573 μL) was added (S)-2-amino-2-(3-bromo-5-fluorophenyl)ethanol HCl salt (18.59 mg, 0.069 mmol), aza-HOBt (11.69 mg, 0.086 mmol), EDC (21.95 mg, 0.115 mmol), and DIEA (30.0 μl, 0.172 mmol). The reaction mixture was stirred for 15 h. Water was added, and the reaction mixture was extracted with EtOAc three times. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC. Pure fractions were lyophilized to provide 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (16.1 mg, 0.023 mmol, 41%) as a TFA salt. LCMS (m/z): 565.1/567.1 (MH+), 0.72 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.86-7.69 (m, 2H), 7.65-7.47 (m, 2H), 7.40-7.30 (m, 1H), 7.22-7.06 (m, 2H), 5.08 (t, J=5.7 Hz, 1H), 4.41-4.14 (m, 1H), 3.85-3.67 (m, 2H), 3.63-3.48 (m, 1H), 2.74 (t, J=11.5 Hz, 1H), 2.17 (td, J=3.1, 6.3 Hz, 1H), 2.04-1.89 (m, 1H), 1.84-1.66 (m, 2H), 1.65-1.30 (m, 2H). The absolute stereochemistry was determined based on the information of X-ray co-structure in ERK2 of 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)-2-fluorobenzamide.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:2].[CH3:18][C@H:19]([NH:28][CH3:29])[C@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1C=CC=CC=1>[CH3:29][N:28]1[CH:19]([CH3:18])[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:2][CH:1]1[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CCOP(=O)(Cc1ccccc1C=O)OCC
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCOP(=O)(Cc1ccccc1C1OC(c2ccccc2)C(C)N1C)OCC
Reaction time: 24 h

Procedure:
2.0 g (8 mmol) of the compound A and 1.32 g (8 mmol) of (-)-ephedrine were dissolved in 100 ml of benzene and heated under reflux in a water separator for 24 h. The solvent was then removed by rotary evaporation and the residue was chromatographed on silica gel (eluent CH2Cl2 /ethanol 9.5/0.5; Rf=0.55). The product F was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[CH:4][C:5]([NH:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:29](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([N:20]3[C:3]4[CH:4]=[C:5]([NH:10][C@H:11]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)[CH3:12])[C:6]([C:7]#[N:8])=[CH:9][C:2]=4[N:1]=[CH:29]3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)cc1C#N)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](Nc1cc2c(cc1C#N)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Yield: 81.9 %

Procedure:
A mixture of (s)-5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]benzonitrile (Method 69; 3.85 g, 10.2 mmol) and formamidine acetate (2.13 g, 20.5 mmol) in EtOH (50 ml) was heated at reflux for 2 hrs. After cooling, the reaction mixture was treated with saturated sodium bicarbonate solution (10 ml) and EtOAc (30 ml). The organic layer was separated, washed with brine (10 ml), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc:MeOH=30:1) to give the title compound as an off-white solid (3.23 g, 82%). NMR (400 MHz) 12.79 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.53 (m, 2H), 7.14 (m, 2H), 7.01 (s, 1H), 6.10 (s, 1H), 6.09 (d, J=7.6 Hz, 1H), 4.63 (m, 1H), 1.97 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 1.03 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 386; Found: [M+H]+ 387.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([C:18]([CH2:20][C:21]2[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[CH:23][CH:22]=2)=[O:19])[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1>CCOCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[CH:16][CH:17]=2)([OH:19])[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[CH:27][CH:28]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Solvent: CCOCC
Product: COc1ccc(CC(O)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
To the Grignard reagent prepared from 20 g 4-bromoanisole (107 mmol) and 2.43 g Mg turnings (107 mg-atom) in 20 mL Et2O was added 19.25 g dry (P2O5) desoxyanisoin (76 mmol) as a solid in four portions, each followed by a 50 mL wash of Et2O. The mixture was stirred at reflux 17 h, cooled to room temperature, poured onto 200 g ice and 40 mL 1N H2SO4, and filtered into a separatory funnel. 100 mL Et2O was added and the organic layer was washed with 100 mL H2O and saturated NaHCO3 (2×100 mL). The organic layer was dried (MgSO4), filtered, and the Et2O was removed under reduced pressure to give crude 1,1,2-Tris(4-methoxyphenyl)ethanol as an orange oil which crystallized (25 mL EtOH with a trace of NH4OH) as an orange solid, 18.6 g (67% crude yield), mp: 109°-127° C.; NMR δ7.47 to 6.63 (m, 12H, ArH), 3.73 (3 overlapping s, 9H, OCH3), 3.48 (s, 2H, CH2), 2.27 (s, 1H, OH). p-TsOH.H2O (2 g; 10.5 mmol) and 18.5 g of the crude carbinol (50.8 mmol) were dissolved in 50 mL C6H6, heated to reflux 2 h, cooled to room temperature, and poured onto 75 mL 5% NaHCO3. The organic layer was washed with 75 mL 5% NaHCO3. The combined aqueous layers were extracted with 25 mL C6H6. The combined organic layers were washed with 100 mL H2O, dried (Na2SO4), filtered, and the solvent removed to give a dark oil. The oil was purified on 80 g flash SiO2 (gradient elution with petroleum ether-CH2Cl 2) yielding an amber oil which solidified at room temperature to yield 1,1,2-Tris(4-methoxyphenyl)ethene as white cubes (11.3 g, 64%), mp: 100°-101° C. (lit. 100°-101° C.). NMR δ7.29 to 6.55 (m, 13H, ArH and C=CH), 3.78 (s, 3H, geminal ring OCH3), 3.75 (s, 3H, vicinal ring OCH3), 3.69 (s, 3H, central ring OCH3).
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[CH2:3]([C:2]1[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:13]([OH:21])[C:8]2[C:7]([CH:1]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1ccccc1C(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCc1cc2ccccc2c(O)c1-c1ccccc1
Yield: 68.3 %

Procedure:
A solution of 1-[2-(1-hexyn-1-yl)phenyl]-2-phenylethanone (171) (0.88 g, 3.18 mmol) in toluene was treated with a KHMDS solution in toluene to give 0.60 g (68%) of the title compound (172) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 0.76 (t, J=7.3 Hz, 3H), 1.15-1.30 (m, 2H), 1.45-1.55 (m, 2H), 2.49 (t, J=7.8 Hz, 2H), 5.20 (s, 1H), 7.33 (s, 1H), 7.36 (d, J=7.0 Hz, 2H), 7.39-7.50 (m, 3H), 7.50-7.57 (m, 2H), 7.75 (d, J=7.9 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H). LCMS (ESI): m/z 277 (M+H)+, m/z 275 (M−H)−.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([O:20][CH3:21])[C:9]([CH3:19])=[C:10]([O:17][CH3:18])[C:11]=2[CH2:15][CH3:16])[S:4]1(=[O:6])=[O:5].[Na].[C:23]1([N:29]2[C:33]([SH:34])=[N:32][N:31]=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[C:23]1([N:29]2[C:33]([S:34][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([O:20][CH3:21])[C:9]([CH3:19])=[C:10]([O:17][CH3:18])[C:11]=4[CH2:15][CH3:16])[S:4]3(=[O:6])=[O:5])=[N:32][N:31]=[N:30]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCc1c(OC)c(C)c(OC)c2c1C(=O)N(CCl)S2(=O)=O
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1c(OC)c(C)c(OC)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 76 %

Procedure:
By the method of Example 44 condensation of 2-chloromethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin (0.17 g) and 1-phenyltetrazol-5-thiol sodium salt (0.084 g) in dimethylformamide (4 mL) and purification of the product by flash column chromatography on silica gel using hexane-ethyl acetate (75:25) as eluant afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin, 0.15 g, 76% yield, mp 44°-46° C.
Reaction SMILES: [CH2:1]([C:3]([OH:28])([CH2:26][CH3:27])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=[CH:10][CH:11]=1)[CH3:2].O.NN>>[NH2:15][CH2:14][CH2:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C:3]([OH:28])([CH2:26][CH3:27])[CH2:1][CH3:2]
Reactant: CCC(O)(CC)COc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Product: CCC(O)(CC)COc1cccc(CCCN)c1

Procedure:
Deprotection of 2-(3-(3-(2-ethyl-2-hydroxybutoxy)phenyl)propyl)isoindoline-1,3-dione using hydrazine hydrate following the method described in Example 18 gave Example 32. 1H NMR (400 MHz, DMSO-d6) δ 7.13 (t, J=6.8 Hz, 1H), 6.69-6.73 (m, 3H), 4.28 (brs, 1H), 3.66 (s, 2H), 2.99 (t, J=4.8 Hz, 2H), 2.47-2.55 (m, 4H), 1.45-1.51 (m, 4H), 0.80 (t, 0.1=7.6 Hz, 6H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>C1COCC1>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc[nH]1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccn1CCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 6.7 g (241.7 mmol) of NaH (60%) in 400 mL of anhydrous THF at 0° C. there are added 20 g (161.13 mmol) of methyl 1H-pyrrole-2-carboxylate (see Tetrahedron 2008, 64, 7745). The whole is subsequently stirred at ambient temperature for one hour. Then, there are added 95 mL of 1,4-dibromobutane. After the addition, the reaction mixture is heated at reflux for 12 hours. The precipitate obtained is filtered off and then washed with THF. The filtrate is subsequently concentrated to dryness. The compound is then isolated by chromatography over silica gel (cyclohexane/ethyl acetate gradient: 0 to 20%) in the form of an oil.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH:32]=1>>[F:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][C:33]2[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=2)[CH2:30][O:1][N:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[N:13][N:14]([CH:16]5[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]5)[CH:15]=4)[CH:9]=3)[CH:4]=[CH:3]2)=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Reactant: Fc1ccc(Oc2cccc(CBr)c2)cc1
Product: Fc1ccc(Oc2cccc(COn3ccc4ncc(-c5cnn(C6CCNCC6)c5)cc43)c2)cc1

Procedure:
The entitled compound is prepared from tert-butyl 4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate and 1-(bromomethyl)-3-(4-fluorophenoxy)benzene as described in the last 2 steps of Example 18.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].[CH2:13](OC(C1NC2C(C=1)=CC=CC=2)=O)[CH3:14]>>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([CH:11]=[O:12])=[CH:6]1)[CH3:14]
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: CCn1cc(C=O)c2cc(F)ccc21
Yield: 57 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 5-fluoro-1H-indole-3-carboxaldehyde (0.41 g, 2.5 mmole) for the ethylindole-2-carboxylate, the title compound (0.20 g, 57%) was prepared as a viscous oil: MS (ES) m/e 191 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[CH:4][CH:3]=1.OP=O.[Si]([O:30][NH2:31])(C)(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C@H:9]([CH2:13][CH3:14])[C:10]([NH:31][OH:30])=[O:11])=[CH:4][CH:3]=1
Reactant: CC[C@H](C(=O)O)[C@H](C(=O)N1CCOCC1)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)ON
Agent: O=PO
Solvent: ClCCl
Product: CC[C@H](C(=O)NO)[C@H](C(=O)N1CCOCC1)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
The crude acid 1b (310 mg, 0.95 mmol) was dissolved in 5 ml of dichloromethane. HOPO (111 mg, 1 mmol) and MEI (0.159 ml, 1.14 mmol) were added successively. The mixture was stirred for 30 minutes, then TMSONH2 (0.233 ml, 1.9 mmol) was added. After one hour another portion of TMSONH2 (0.233 ml, 1.9 mmol) was added and stirring continued over night. The reaction mixture was filtered (solid contained mostly HOPO) diluted with 20 ml of dichloromethane and extracted twice with 2N-HCl and brine, dried over anhydrous sodium sulfate and evaporated. The crude solid (237 mg, 73%) was purified by preparative HPLC (methanol/water=1/1). Yield: 100 mg (31%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[CH3:12][N:13]1[C:17]([CH:18]=[O:19])=[CH:16][N:15]=[CH:14]1>C1COCC1>[CH3:1][N:2]1[C:6]([CH:18]([C:17]2[N:13]([CH3:12])[CH:14]=[N:15][CH:16]=2)[OH:19])=[CH:5][N:4]=[N:3]1
Reactant: Cn1cncc1C=O
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1cnnn1C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-methyl-1H-1,2,3-triazole (1.47 g, 17.7 mmol, PCT Int. Appl. 2008098104) in 20 mL THF was cooled to −40° C. in a dry-ice/acetonitrile bath. n-Butyllithium (1.6 M in hexane, 10.2 mL, 16.3 mmol) was added dropwise via syringe and the mixture was stirred at −40° C. for 30 minutes. A solution of 1-methyl-1H-imidazole-5-carbaldehyde (1.50 g, 13.6 mmol) in 10 mL THF was then added and the mixture was stirred for 5 minutes, then was transferred to an ice/water bath. After 1 hour, the mixture was quenched by addition of saturated aqueous NH4Cl, diluted with water, and extracted twice with EtOAc. The aqueous phase, which contained the title compound, was then concentrated. The residue was purified by flash column chromatography (silica gel, gradient 3-10% MeOH-DCM) to afford the title compound as a light yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][CH:12]([CH:14]=O)[CH2:11]3)[N:7]([CH3:16])[C:6]=2[CH:17]=1.Cl.[NH2:19][OH:20]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][CH:12]([CH:14]=[N:19][OH:20])[CH2:11]3)[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: Cn1c(C2CC(C=O)C2)nc2ccc(Br)cc21
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Cn1c(C2CC(C=NO)C2)nc2ccc(Br)cc21

Procedure:
To a stirred solution of 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbaldehyde (less polar isomer, 200 mg) in EtOH (10 ml) was added hydroxylamine hydrochloride (50 mg), and the resulting mixture was heated under reflux for 2 h. The reaction mixture was concentrated in vacuo to afford the title compound (200 mg) as an off-white solid.
Reaction SMILES: II.P(Cl)(Cl)([Cl:5])=O.[F:8][C:9]([F:23])([F:22])[C:10]1[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=1[NH:12][CH2:13][CH2:14][C:15](O)=O.S(=O)(O)[O-].[Na+]>O>[Cl:5][C:15]1[C:18]2[C:11](=[C:10]([C:9]([F:23])([F:22])[F:8])[CH:21]=[CH:20][CH:19]=2)[N:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CCNc1ccccc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cccc2c(Cl)ccnc12
Reaction time: 0.5 h

Procedure:
13.75 g of monosublimated iodine were added at 0° to 5° C. to75 ml of phosphorus oxychloride and the mixture was heated over 30 minutes to 93°-95° C. and was held at 93°-95° C. for about 30 minutes. Then, 50 g of the product of Step A were added over 6 minutes in fractions of 1.250 g to the mixture and then the mixture was held at 93°-95° C. for 30 minutes. After cooling to 70°±5° C., the mixture was added over about 30 minutes toa stirred solution of 11 g of sodium bisulfite in 875 ml of water held at 40° to 45° C. The mixture was cooled over 30 minutes to 15°-20° C. to obtain a gummy suspension which was vacuum filtered washed and dried. The product was crystallized from methanol to obtain 36.9 g of 4-chloro-8-trifluoromethyl-quinoline with a 98% purity.
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])[CH2:2][CH3:3].[Li]>O1CCCC1.NC1C=CC=CC=1.N>[CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])[CH2:2][CH3:3]
Reactant: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Li]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CCC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Add 13β-n-propyl-3-methoxy-gona-1,3,5(10),8-tetraen-17β-ol (3.1 g.) dissolved in a mixture of tetrahydrofuran (10 cc.) and freshly distilled aniline (60 cc.) to liquid ammonia (160 cc.) and add lithium metal (1.5 g.) in small pieces. Stir the reaction mixture for 3 hours, then quench with solid ammonium chloride (12.5 g.) and take up in water. Ether-extract the product and evaporate the washed and dried extracts to obtain a semisolid residue of crude 13β-n-propyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (3.1 g.); ultraviolet absorption peak at 279 mμ (ε1,800).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([P:13]([C:16]3[CH:25]=[C:24]4[C:19]([C:20]([CH3:30])=[CH:21][C:22]([CH3:29])([CH3:28])[N:23]4[CH2:26][CH3:27])=[CH:18][CH:17]=3)(=[O:15])[OH:14])[CH:11]=2)[C:6]([CH3:31])=[CH:5][C:4]1([CH3:33])[CH3:32])[CH3:2]>CO.[Pt]>[CH2:26]([N:23]1[C:24]2[C:19](=[CH:18][CH:17]=[C:16]([P:13]([C:10]3[CH:11]=[C:12]4[C:7]([CH:6]([CH3:31])[CH2:5][C:4]([CH3:33])([CH3:32])[N:3]4[CH2:1][CH3:2])=[CH:8][CH:9]=3)(=[O:14])[OH:15])[CH:25]=2)[CH:20]([CH3:30])[CH2:21][C:22]1([CH3:28])[CH3:29])[CH3:27]
Reactant: CCN1c2cc(P(=O)(O)c3ccc4c(c3)N(CC)C(C)(C)C=C4C)ccc2C(C)=CC1(C)C
Agent: [Pt]
Solvent: CO
Product: CCN1c2cc(P(=O)(O)c3ccc4c(c3)N(CC)C(C)(C)CC4C)ccc2C(C)CC1(C)C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
To a solution of the compound bis(1-ethyl-2,2,4-trimethyl-1,2-dihydroquinolin-7-yl)phosphinic acid (4.22 g, 9.1 mmol) (Example 5) in methanol (100 mL), was added platinum (0.42 g, 5 wt. % on activated carbon). The mixture was stirred under hydrogen (50 psi) for 5 hours. The mixture was filtered through a pad of celite and then evaporated to dryness to give white solid (4.09 g, 96% yield). It is used without further purification. The structure of bis(1-ethyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)phosphinic acid is:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][S:14]([O:17][CH:18]([CH:20]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:21][CH2:22][O:23][Si](C(C)C)(C(C)C)C(C)C)[CH3:19])(=[O:16])=[O:15].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH3:13][S:14]([O:17][CH:18]([CH:20]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:21][CH2:22][OH:23])[CH3:19])(=[O:16])=[O:15]
Reactant: CC(OS(C)(=O)=O)C(CCO[Si](C(C)C)(C(C)C)C(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(OS(C)(=O)=O)C(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
0.24 g of p-toluenesulfonic acid monohydrate was added to a solution of 1.05 g of 3-phenyl-5-((tris(propan-2-yl)silyl)oxy)pentan-2-yl methanesulfonate in 15 mL of methanol, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/4 to 1/1), so as to obtain 0.56 g of 5-hydroxy-3-phenylpentan-2-yl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[F:13][CH:14]([F:29])[C:15]1[CH:16]=[C:17]([NH:21][C:22]2[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH:23]=2)[CH:18]=[CH:19][CH:20]=1.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:23]3[C:24](=[O:28])[CH2:25][CH2:26][CH2:27][C:22]=3[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]([F:13])[F:29])[CH:16]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(Nc2cccc(C(F)F)c2)CCC1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Product: O=C1CCCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (400 mg, 1.62 mmol) in dichloromethane (2.5 mL) is added to a solution of 3-(3-(difluoromethyl)phenylamino)-cyclohex-2-enone (intermediate 32, 385 mg, 1.62 mmol) in dichloromethane (2.5 mL). The mixture is heated at reflux for 2 h and cooled to room temperature. Water is added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 80:20 to ethyl acetate. Yield: 350 mg; ESI mass spectrum: [(79Br)-M+H]+=447, [(81Br)-M+H]+=449; Retention time HPLC: 0.61 min (X012_S01).