Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:11]([S:13](Cl)(=[O:15])=[O:14])[CH3:12]>CN(C)C=O.C(OCC)(=O)C>[CH2:11]([S:13]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)(=[O:15])=[O:14])[CH3:12]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)n1ccc([N+](=O)[O-])n1
Yield: 76.1 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (39 mg, 0.94 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for an additional 10 min, the ethanesulfonyl chloride (94 μL, 1.00 mmol) was added. The mixture was continued to stir under nitrogen for 16 h. The solution was diluted with ethyl acetate (50 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 1-ethanesulfonyl-3-nitro-1H-pyrazole (139 mg, 77%) as a clear, waxy solid: H1-NMR (400 MHz, CDCl3) δ 1.38 (2H, t, J=7.2 Hz), 3.68 (2H, qt, J=7.2 Hz), 7.05 (1H, d, J=2.8 Hz), 8.14 (1H, d, J=2.8 Hz).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[F:10][C:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:10][C:11]1[CH:16]=[C:15]([C:2]2[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: OB(O)c1ccnc(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1csc(-c2ccnc(F)c2)c1
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-thiophene-3-carboxylic acid (0.71 g, 4.4 mmol), 2-fluoropyridine-4-boronic acid (0.619 g, 4.4 mmol), caesium carbonate (2.9 g, 8.8 mmol), and palladium tetrakis(triphenylphosphine) (0.469 g, 0.44 mmol) in DME (40 mL), IMS 20 mL) and water (10 mL) was divided across three microwave vials and each was heated by microwave irradiation to 120° C. for 20 minutes. The batches were combined and concentrated and the residue was partitioned between saturated aqueous sodium carbonate and DCM. The aqueous phase was isolated and filtered to obtain the title compound as a grey precipitate (0.168 g) and the filtrate was acidified using dilute HCl (pH 2) then re-filtered to obtain a further amount of the title compound as an off-white solid (0.114 g). LCMS m/z 224.06 [M+H]+ R.T.=2.77 min (Analytical Method 8).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC.[F-].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cccs2)cc1
Temperature: 90 °C
Yield: 49.4 %

Procedure:
A mixture of 1-bromo-4-octyloxybenzene (compound 22) (10.0 g, 0.0351 mol), 2-(tributylstannyl)thiophene (14.4 g, 0.0386 mol) and tetrakis(triphenylphosphine)-palladium (0) (1.22 g, 1.05×10−3 mol) in DMF (200 cm3) was heated at 90° C. for 24 h. The mixture was allowed to cool to RT and the solution was treated with a saturated potassium fluoride solution (100 cm3) to destroy the tin side products. Hexane (2×200 cm3) was added and the combined organic layers were washed with brine (2×200 cm3), water (200 cm3), dried (MgSO4), filtered and concentrated under reduced pressure. Catalyst residues were removed by passing the crude product though a short column containing silica gel [DCM: hexane, 50%: 50%]. The product was recrystallised from ethanol, filtered and washed with cold ethanol (2×30 cm3) to yield a light blue crystalline solid (5.00 g, 49.5%). Melting point/° C.: 68–70.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[C:8]([NH2:11])(=[NH:10])[CH3:9].C[O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]1=O)=O>C(O)C>[CH3:9][C:8]1[N:11]=[C:14]([OH:13])[C:16]2[CH2:21][CH2:20][CH2:19][C:18]([CH3:28])([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:17]=2[N:10]=1
Reactant: COC(=O)C1CCCC(C)(c2ccccc2)C1=O
Reactant: CC(=N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1nc(O)c2c(n1)C(C)(c1ccccc1)CCC2
Yield: 52.4 %

Procedure:
A solution of potassium t-butoxide (8.4 g, 75 mmol), acetamidine hydrochloride (7.1 g, 75 mmol) and 3-methyl-2-oxo-3-phenyl-cyclohexanecarboxylic acid methyl ester (30 mmol) in 150 mL of ethanol was stirred at room temperature for 12 hours and then heated under reflux for 2 hours. The mixture was concentrated under reduced pressure, diluted with water, and washed with ether. The aqueous layer was neutralized with HCl and filtered to afford 4.0 g of 2,8-dimethyl-8-phenyl-5,6,7,8-tetrahydro-quinazolin-4-ol as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: O=C(CCl)c1ccccc1
Reactant: Oc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(COc1ccc2c(c1)C=CC2)c1ccccc1

Procedure:
Using the method of Example 1, step A, 5-hydroxyindane is reacted with α-chloroacetophenone in benzene in the presence of sodium carbonate to provide α-(5-indenoxy)acetophenone as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:23][C:24]([NH2:26])=[S:25])=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][C:29](=O)[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C.C(O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:23][C:24]2[S:25][CH:28]=[C:29]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:26]=2)=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)CBr
Reactant: NC(=S)Nc1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CCc1csc(Nc2ncc(Oc3ccccc3Cl)cc2OCc2ccccc2)n1
Yield: 71.2 %

Procedure:
A mixture of 1-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-yl)thiourea (0.471 g, 1.11 mmol), methyl 5-bromo-4-oxopentanoate (0.279 g, 1.33 mmol), triethylamine (0.271 ml, 1.94 mmol), and ethanol (10 mL) was heated at reflux for 2 hours, cooled, partitioned between ethyl acetate and 2N NaOH, washed with water and brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 3:1 hexane:ethyl acetate to afford methyl 3-(2-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-ylamino)thiazol-4-yl)propanoate (0.392 g, 71.2% yield) as a white viscous oil/wax. The compound (70 mg) was dissolved in ether (2 mL) and 1N HCl in ether (0.5 mL) was added. The mixture was stirred 5 minutes, and hexanes (5 mL) were added. The mixture was decanted, and a mixture of hexanes:ether (2:1, 3 mL) was added three times with three decantations. The solid material was dried to afford methyl 3-(2-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-ylamino)thiazol-4-yl)propanoate hydrochloride (0.058 g, 9.81% yield) as a white solid. 1H NMR (DMSO-d6) δ 2.73 (t, 2H), 3.61 (s, 3H), 2.91 (t, 2H), 5.32 (s, 2H), 6.82 (s, 1H), 6.99 (d, 1H), 7.21 (t, 1H), 7.31-7.43 (m, 4H), 7.47 (d, 1H), 7.55-7.66 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)=[O:13])[CH3:16]
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
0.593 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 7.5 ml of N,N-dimethylformamide; 0.535 g of N,N′-carbonyldiimidazole and 0.46 g of glycine ethyl ester hydrochloride were added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.457 ml of triethylamine was added, followed by further stirring for 1 hour. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 0.749 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16](OC)=[O:17])[CH:15]=[C:10]3[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[NH2:22][OH:23].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([NH:22][OH:23])=[O:17])[CH:15]=[C:10]3[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)c1cc2cnn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NO)c1cc2cnn(Cc3ccc(F)cc3)c2cn1
Reaction time: 2 h
Yield: 52 %

Procedure:
To a stirring solution of methyl 1-(4-fluorobenzyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylate (96 mg, 0.33 mmol) in methanol (4 mL) was added a 50% v/v solution of hydroxylamine in water (2 mL) followed by 10% sodium hydroxide solution in water (1 mL). The mixture was stirred for 2 hours, then 10% hydrochloric acid solution in water (1 mL) was added until a neutral pH was obtained, and the mixture was concentrated under reduced pressure. Methanol was added and the mixture was purified by reverse phase preparative HPLC (Dionex, 0-40% acetonitrile:water v/v, 40 minutes) to provide a white solid (50 mg, 52% yield). 1H NMR (DMSO-d6): δ ppm 9.22 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 7.37 (m, 2H), 7.15 (m, 2H), 5.83 (s, 2H). Anal. HPLC: >95% (@ 254, 222 nM). HRMS calcd for C14H11FN4O2 (M+H) 287.0939, found 287.0936.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]([NH:18][CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:20][C:21]([O:23]C)=[O:22])=[O:17])=[O:13])[CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]([NH:18][CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:20][C:21]([OH:23])=[O:22])=[O:17])=[O:13])[CH:3]=1
Reactant: COC(=O)CC(NC(=O)CNC(=O)CCCNc1cc(C)ccn1)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccnc(NCCCC(=O)NCC(=O)NC(CC(=O)O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
280 mg of methyl 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(2-nitrophenyl)propionate (crude material) are dissolved in 30 ml of dioxane, and 0.61 ml of NaOH (2 mol/l) is added. Stirring at room temperature overnight is followed by removal of the solvent by distillation and the usual workup. 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(2-nitrophenyl)propionic acid is obtained. If an excess of NaOH is used, the sodium salt of 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(2-nitrophenyl)propionic acid is obtained. Preparative HPLC results in 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(2-nitrophenyl)propionic acid trifluoroacetate, RT 16.14 min, FAB-MS (M+H)+ 444.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:33][NH:34][CH2:35][CH2:36][C:37]1([OH:51])[CH2:42][CH:41]2[CH2:43][CH2:44][CH:38]1[CH:39]=[C:40]2[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[N:34]([CH2:35][CH2:36][C@:37]1([OH:51])[CH2:42][C@H:41]2[CH2:43][CH2:44][C@@H:38]1[CH:39]=[C:40]2[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH3:33])([CH3:5])([CH3:6])[CH3:7]
Reactant: CNCCC1(O)CC2CCC1C=C2c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC[C@]1(O)C[C@H]2CC[C@@H]1C=C2c1ccccc1)C(=O)CCNC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
To a solution of 159 mg of BOC-beta-alanine in 4 mL DCM were added 0.36 mL DIPEA and 113 mg of HOBt. After stirring for 15 min, 300 mg of rac-(1R*,2R*,4R*)-2-(2-methylamino-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol in 4 mL DCM were added followed by 161 mg of EDCI. The resulting suspension was stirred for 2 h at rt, then quenched with water. The water phase was reextracted with DCM, the combined organic phases were washed with sat. aq. NaHCO3, dried and concentrated in vacuo. The residue was purified by preparative TLC with EtOAc to give 168 mg of rac-(2-{[2-((1R*,2R*,4R*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-carbamoyl}-ethyl)-carbamic acid tert.-butyl ester as white foam.
Reaction SMILES: Br[C:2]1[NH:6][C:5]([CH2:7][C:8]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)([OH:12])[CH:9]([F:11])[F:10])=[N:4][C:3]=1[CH2:24][C:25]1([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]1.[CH3:32][Sn](C)(C)C.[Cl-].[Li+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(OCC)C>[F:10][CH:9]([F:11])[C:8]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1)([OH:12])[CH2:7][C:5]1[NH:6][C:2]([CH3:32])=[C:3]([CH2:24][C:25]2([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]2)[N:4]=1
Reactant: OC(Cc1nc(CC2(C(F)(F)F)CC2)c(Br)[nH]1)(c1ccc(-n2cccn2)cc1)C(F)F
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1[nH]c(CC(O)(c2ccc(-n3cccn3)cc2)C(F)F)nc1CC1(C(F)(F)F)CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Bis(triphenylphosphine)palladium(II)dichloride (94 mg, 0.13 mmol) was added to a solution of 3-(5-bromo-4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)-1,1-difluoro-2-[4-(1H-pyrazol-1-yl)phenyl]propan-2-ol (202 mg, 0.45 mmol), tetramethyltin (319 mg, 1.78 mmol), lithium chloride (151 mg, 3.57 mmol), and triphenylphosphine (47 mg, 0.18 mmol) in degassed N,N-dimethylformamide (10 mL) at ambient temperature. The solution was stirred at 120° C. for 2 hr. The solution was cooled to ambient temperature and saturated aqueous potassium fluoride (10 mL) was added. The mixture was stirred for 1 hr at ambient temperature. Diethyl ether and water was added and the layers were separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo. Chromatography over C-18 silica eluting with 10-100% acetonitrile/water afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.22 (d, J=2.5 Hz, 1H), 7.77-7.72 (m, 2H), 7.62-7.51 (m, 3H), 6.53 (t, J=2.0 Hz, 1H), 6.14 (t, J=55.2 Hz, 1H), 3.57-3.48 (m, 2H), 2.90 (dd, J=15.7, 60.7 Hz, 2H), 2.16 (s, 3H), 0.86 (dd, J=5.0, 5.0 Hz, 2H), 0.52 (dd, J=9.5, 33.0 Hz, 2H). Individual enantiomer (E1 or E2) was obtained by HPLC separation on a chiral column.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5](NCCC)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[N:3]1.[Na]>>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[N:3]1
Reactant: CCCNc1c(-c2cccc(C(F)(F)F)c2)nn(C)c1C(=O)O
Agent: [Na]
Product: Cn1nc(-c2cccc(C(F)(F)F)c2)cc1C(=O)O

Procedure:
1-methyl-3-(3-trifluoromethylphenyl)-4-propylaminopyrazole-5-carboxylic acid, sodium salt
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]1([CH:18]([N:20]=[C:21]=[O:22])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH:18]([NH:20][C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:22])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: CC(N=C=O)c1ccccc1
Product: CC(NC(=O)Nc1ccc2ncccc2c1)c1ccccc1

Procedure:
Prepared from 6-aminoquinoline and (+/−)-1-phenylethyl isocyanate. m/z (ES+) 292 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25].CS(C)=O.[N-:40]=[N+:41]=[N-:42].[Na+].CCCCCC>C(OCC)(=O)C>[N:40]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCOCCCCBr)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCOCCCCN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To (3RS,4RS)-4-(9-bromo-5-oxanonyl)-7-methoxymethoxy-3-(4-(methoxymethoxy)phenyl)-3-methylchroman (276 mg, 0.5 mmol) in. DMSO was added sodium azide (65.1 mg, 1 mmol). The mixture was stirred at 80° C. for 3 h. After cooling, the mixture was extracted with ethyl acetate, dried over MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the concentrate thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give 269 mg (yield. 100%) of a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([P:11](=[O:18])([O:15]CC)[O:12]CC)[CH:6]=[C:7]([F:10])[C:8]=1[F:9]>>[F:2][C:3]1[CH:4]=[C:5]([P:11](=[O:12])([OH:18])[OH:15])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: CCOP(=O)(OCC)c1cc(F)c(F)c(F)c1
Agent: Cl
Product: O=P(O)(O)c1cc(F)c(F)c(F)c1
Yield: 75.1 %

Procedure:
12 M HCl (12 mL, excess) was added to diethyl 3,4,5-trifluorophenylphosphonate (320 mg) in a round bottom flask. The reaction mixture was refluxed for 12 hours. A brown oil was obtained after cooling and removal of the solvent. 1H NMR showed the presence of unreacted starting material. 12 mL of 8 M HCl was added and the reaction mixture refluxed again for several days. The mixture was allowed to cool and stand for several weeks. An off-white solid was obtained after removal of the solvent (190 mg, 76% yield). 1H NMR (400.14 MHz, DMSO) δ 7.49-7.42 (m, 2H). 13C{1H} NMR (100.62 MHz, DMSO) δ 150.1 (dddd, J=251.0, 23.7, 7.3, 2.6 Hz, 2C), 140.5 (dtd, J=253.1, 15.3, 2.6 Hz), 131.8 (dm, J=178.4 Hz), 115.3-114.9 (m, 2C). 31P{1H} NMR (161.97 MHz, DMSO): δ 9.22. Analysis calculated (found) %: C, 33.98 (33.94), H, 1.90 (1.80). MS (FAB, m/z): 213 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 212.99284 (212.99418).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[N:15]=[N+]=[N-])=[CH:4][CH:3]=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Reaction time: 18 h

Procedure:
A solution of (1R,2S)-2-azidocyclohexyl 4-bromophenyl ether from the previous step (2.85 g, 9.62 mmol) in tetrahydrofuran (59 mL) and water (4.6 mL) was treated with polymer-supported triphenylphosphine (3 mmol/g, 7.87 g, 23.6 mmol). The reaction was stirred for 18 hours, then filtered through Celite®. The filter pad was rinsed with tetrahydrofuran (250 mL), then with ethyl acetate (400 mL), and the combined filtrates were concentrated in vacuo, and azeotroped with ethanol. The residue was purified by chromatography on silica gel (Gradient: 0% to 10% methanol in dichloromethane) to afford (1S,2R)-2-(4-bromophenoxy)cyclohexanamine as a yellow oil. Yield: 1.82 g, 6.74 mmol, 70%. 1H NMR (400 MHz, CDCl3) δ 1.33-1.55 (m, 4H), 1.66-1.75 (m, 3H), 2.00 (m, 1H), 2.07 (br s, 2H), 2.97 (m, 1H), 4.39 (m, 1H), 6.85 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H).
Reaction SMILES: COC1C=CC(C2C(C)(C)C3C(CC=2)=CC(OC)=CC=3)=C(N)C=1.Cl.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:29](O)=O.FC1C=[C:47](C=CC=1OCCN1CCCCC1)[CH2:48][NH:49][C:50]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[CH:52][C:51]=1[C:58]1[C:59]([CH3:71])([CH3:70])[C:60]2[C:65]([CH2:66][CH:67]=1)=[CH:64][C:63]([O:68][CH3:69])=[CH:62][CH:61]=2>>[CH2:48]([N:49]([CH2:29][C:28]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:26]([F:25])[CH:27]=1)[C:50]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[CH:52][C:51]=1[C:58]1[C:59]([CH3:70])([CH3:71])[C:60]2[C:65]([CH2:66][CH:67]=1)=[CH:64][C:63]([O:68][CH3:69])=[CH:62][CH:61]=2)[CH3:47]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc2c(c1)CC=C(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2(C)C
Agent: COc1ccc(C2=CCc3cc(OC)ccc3C2(C)C)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1=CCc2cc(OC)ccc2C1(C)C

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,1-dimethyl-1,4-dihydronaphthalen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,4-dihydronaphthalen-2-yl)phenyl]amine (316 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,4-dihydronaphthalen-2-yl)phenyl]amine (82 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (62 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1.[CH3:15]I.[NH4+].[Cl-]>CN(C=O)C>[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]([CH3:15])[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=c1[nH]ccc2ccc(F)cc12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(F)cc2c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.6 %

Procedure:
Under N2, sodium hydride (710 mg, 29.4 mmol) was added to 7-fluoro-2H-isoquinolin-1-one (4 g, 24.55 mmol) in dry DMF (40 mL) at 0° C. After stirring at 0° C. for 20 min, CH3I (5.2 g, 36.7 mmol) was added. The mixture was stirred at 26° C. for 2 h. Saturated aqueous NH4Cl (20 mL) was added and after extractive work up with ethyl acetate, purification by silica gel chromatography (PE:EA=10:1) gave the title compound (2.2 g, 50%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 8.06 (dd, J1=9.6 Hz, J2=2.8 Hz, 1H), 7.50 (dd, J1=8.8 Hz, J2=5.2 Hz, 1H), 7.38-7.36 (m, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.48 (d, J=7.2 Hz, 1H), 3.61 (s, 3H). LCMS: 178.1 [M+H]+