Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][CH2:20][CH2:21][C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][O:19][CH3:18])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: COCCC(=O)O
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: COCCC(=O)Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reaction time: 0.17 h
Yield: 20 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (37 mg, 1.1 eq, 0.16 mmol) was added to a solution of 3-methoxypropionic acid (15.5 mg, 1.0 eq, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg, 1.0 eq, 0.16 mmol), 1-hydroxybenzotriazole (20 mg, 1.0 eq, 0.15 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added, and solvent was removed in vacuo. The resultant solid was washed with water and purified by semi-preparative HPLC to yield the title compound as a white solid (9.3 mg, 0.03 mmol, 20%). LCMS: [M+H]+=313, Rt=1.31 min, 100% purity.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl>O>[CH:8](=[C:7]1[NH:1][C:2](=[S:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CNC(=S)N1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1NC(=S)NC1=Cc1ccccc1

Procedure:
A flask equipped with a magnetic stirrer, nitrogen pressure, and reflux condenser was charged with thiohydantoin (24.9 g, 0.215 mol), benzaldehyde (22.8 g, 0.215 mol), triethylamine (43 g, 0.43 mol), and water (250 mL). Slight warming and vigorous stirring brought everything into solution. The mixture was stirred overnight and then transferred to an Erlenmeyer flask equipped with a magnetic stirrer. The pH was brought to ca. 3 with 3 M hydrochloric acid, and the mixture was stirred for 3 hr. The resulting solid was collected and washed with water and 2×50 mL of diethyl ether. The product weighed 97.6 g (97%). No other components were found in an HPLC trace at 260 and 350 nm. NMR (d6-DMSO) δ 7.2-7.8 (m, 5H), 6.4 (s, 1H), 3.5 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH2:13])=O)[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.O=P(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:13])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: NC(=O)c1cc(Br)c2c(c1)CCC2
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1cc(Br)c2c(c1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
7-Bromoindane-5-carboxamide (1.94 g, 8.1 mmol) was suspended in CH2Cl2 (50 mL) whereupon POCl3 (1.5 g, 9.8 mmol) was added. Triethylamine (3.5 g, 34.6 mmol), dissolved in CH2Cl2 (10 mL) was added during one minute and an exotermic reaction was observed. The mixture was stirred at room temperature for 30 min and then poured over ice (50 g). The remaining material in the flask was washed out using CH2Cl2 (50 mL) and water (25 mL). The organic layer was washed twice with brine, dried over Na2SO4 and then the solvent was evaporated. The solid residue was treated with cold methanol and then filtrated off. The material was washed with cold methanol and then dried. There was obtained 1.2 g (66%) of 7-bromoindane-5-carbonitrile as a solid material. 1H NMR (300 MHz, CDCl3): 2.1-2.2 (q, 2H), 2.9-3.1 (m, 4H), 7.4 (s, 1H), 7.6 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2Br)[CH2:3]1.[CH3:29][C:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[N:32](C2CCCCO2)[N:31]=1>>[NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2[C:33]2[NH:32][N:31]=[C:30]([CH3:29])[CH:34]=2)[CH2:3]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Reactant: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2Br)C[C@@H]1O
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)ccc2N2C[C@H](N)[C@@H](O)C2)[nH]n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 76 using 4-((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (Stage 76.1) and 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford the title compound as white solid. HPLC (Condition 7) tR=5.763 min, UPLC-MS (Condition 8) tR=0.82 min, m/z=478.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.52 (br. s, 2H) 2.26 (br. s, 3H) 2.71-2.86 (m, 2H) 3.10 (br. s, 1H) 3.23-3.38 (m, 2H) 3.67-3.79 (m, 1H) 4.95 (br. s, 1H) 6.09 (s, 1H) 6.77 (d, J=8.21 Hz, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.77-7.94 (m, 4H) 10.08 (s, 1H) 12.45 (br. s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>CC(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([CH:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)=[CH:20][CH:21]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CN1CCC(c2ccc(Nc3nc(Br)cn4ccnc34)cc2)CC1
Yield: 57.5 %

Procedure:
A solution of 6,8-dibromoimidazo[1,2-a]pyrazine (500 mg, 1.8 mmol), 4-(1-methylpiperidin-4-yl)benzenamine (376 mg, 1.98 mmol) and CSA (356 mg, 1.53 mmol) in iPrOH (30 mL) was stirred at 90° C. overnight. The solvent was evaporated. The residue was dissolved in DCM (30 mL), NaHCO3 solution (10 mL) was added to adjust pH=8. The organic layer was dried over Na2SO4 and evaporated. The residue was purified through a silica-gel column (ethyl acetate:petroleum ether=1:1) to afford the desired product as a yellow solid (400 mg, 58% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[N:7]=1.FC(F)(F)[C:16](O)=[O:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:16]=[O:17])=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[N:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1ccc2nc(C3CC3)cn2n1
Product: O=Cc1c(C2CC2)nc2ccc(Cl)nn12
Yield: 45 %

Procedure:
6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine x105 (1.88 g, 9.71 mmol) and hexamethyltetramine (HMTE, 13.61 g, 97.09 mmol, 10 eq) in trifluoroacetic acid (75 ml) are heated at 60° C. during 6 days. After cooling and solvent evaporation under reduced pressure, the crude product is dissolved in dichloromethane (150 ml). The organic layer is washed with water (150 ml) and the resulting aqueous layer is extracted with dichloromethane (150 ml). The cumulated organic layers are dried over MgSO4, filtered and the solvent is removed by evaporation under reduced pressure. The resulting crude compound is purified by preparative chromatography (benzine/AcOEt:80/20) affording 0.82 g of 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine-3-carbaldehyde x110.
Reaction SMILES: [H-].[K+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][OH:16].[CH2:17]([Sn:21]([CH2:30]I)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O1CCCC1.CCCCCC>[CH2:17]([Sn:21]([CH2:30][O:16][CH2:15][CH2:14][CH2:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:18][CH2:19][CH3:20]
Reactant: OCCCc1ccc2ccccc2c1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCCCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium hydride (315 mg, 7.87 mmol) was added to a solution of 3-(2-naphthyl)propan-1-ol (1.33 g, 7.16 mmol) in tetrahydrofuran (10 ml) at room temperature under argon. After 1/2 hour, a solution of tributylstannylmethyliodide (3.09 g, 7.16 mmol) in tetrahydrofuran (2 ml) was added. After stirring at room temperature for 10 days, the mixture was diluted with hexane and washed thoroughly with water. Evaporation of the dried (magnesium sulphate) organic layer gave an oil, which was flash chromatographed on silica using 5% ethyl ether/petroleum ether. The title ether was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12](O)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:34]([CH:12]([C:10]1[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(N=[N+]=[N-])c1cc(Cl)c2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[5-chloro-8-(2-fluorophenyl)quinolin-7-yl]ethanol (0.044 g, 0.14 mmol) in methylene chloride (0.9 mL) was added triethylamine (0.0305 mL, 0.219 mmol), followed by methanesulfonyl chloride (0.0141 mL, 0.182 mmol). After stirring at room temperature for 30 minutes, the resultant mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resulting residue was used directly in next step. LCMS (M+H)+m/z=380.0. The crude mesylate was dissolved in N,N-dimethylformamide (0.4 mL) and treated with sodium azide (0.0474 g, 0.730 mmol) at 60° C. for 1 hour. After diluting with ethyl acetate, the mixture was washed with water and brine and then dried over magnesium sulfate and evaporated to dryness. The crude product was used in the next step. LCMS calculated for C17H13ClFN4(M+H)+: m/z=327.1; found: 327.0.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)[NH:5]1>CS(C)=O>[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)[N:5]1[CH2:23][CH2:22][CH2:6][CH2:7][OH:21]
Reactant: N#Cc1ccc(N2C(=O)NC3(CCSCC3)C2=O)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2C(=O)N(CCCCO)C3(CCSCC3)C2=O)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 148.5 %

Procedure:
Using the procedure of Example 3, 55 mg of 50% sodium hydride and 355 mg of the product of Example 13 were reacted and 2.5 ml of dimethylsulfoxide were added dropwise over 20 minutes. Rinsing was carried out with 0.5 ml of dimethylsulfoxide and 20 minutes after the release of hydrogen had stopped, 0.41 g of 4-iodo-butoxy-trimethylsilane were added. The reaction medium was poured into 25 ml of water containing 0.1 g of monopotassium phosphate and extraction was carried out 3 times with ether. The organic phase was washed with water, then with salt water and dried. The resultant product was taken up in 10 ml of methanol and 1 ml of 2N hydrochloric acid and left for 30 minutes. It was poured into 30 ml of 50% sodium chloride and extraction was carried out 3 times with ethyl acetate. The extracts were washed with salt water and dried. Purification was carried out on silica with methylene chloride-acetone: 9-1 as eluant to obtain 317 mg of the expected product (white crystals) melting at 139°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][CH2:24][CH3:25])[C:13]=2[C:14]([O-:16])=[O:15])[N:4]=1.[CH:26]([NH2+]C(C)C)(C)C.CI>O1CCCC1.CN(C=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][CH2:24][CH3:25])[C:13]=2[C:14]([O:16][CH3:26])=[O:15])[N:6]=1
Reactant: CC(C)[NH2+]C(C)C
Reactant: CCCC#Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)[O-]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: CCCC#Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Yield: 74.4 %

Procedure:
Diisopropylammonium 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-pentynyl)benzoate (1.00 g, 2.3 mmol) was dissolved in tetrahydrofuran (20 ml)-DMF (10 ml) in a 50 ml round bottom-flask, and methyl iodide (1.4 g, 10.0 mmol) was added thereto little by little. The resultant mixture was stirred at 50° C. for 2 hours and THF-DMF was distilled off under reduced pressure. Water was added to the resultant residue, and the residue was extracted with ethyl acetate. The organic layer thus obtained was washed with water and a saturated salt water, dried with anhydrous sodium sulfate and concentrated. To the resultant mixture, was added an appropriate amount of Florisil, and the mixture was eluted with ispropyl ether. The solvent was then distilled off under reduced pressure to obtain 0.61 g (yield: 76.3 %) of the aimed product (yellow viscous liquid).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:26][CH2:27][C@H:28]([OH:38])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:38][C@H:28]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH2:27][NH:26][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from octane-1-sulfonic acid (4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 230) and 4-((2S)-3-amino-2-hydroxy-propoxyl)-phenol (which was obtained in Example 5) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.85 (t, J=7.0 Hz, 3H), 1.15-1.45 (m, 12H), 1.50-1.70 (m, 2H), 1.80-1.95 (m, 2H), 2.50-2.80 (m, 5H), 2.92 (brt, J=6.7 Hz, 2H), 3.54 (brd, J=12.3 Hz, 2H), 3.70-3.90 (m, 3H), 6.66 (d, J=6.7 Hz, 2H), 6.75 (d, J=8.3 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 8.89 (brs, 1H), 9.28 (brs, 1H); MS (ES) m/z: 534.1 (MH+); HRMS Calcd. for C28H44N3O5S(MH+): 534.3002. Found: 534.3017.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[OH:19])=[CH:6][CH:5]=1.COC1C=CC(O)=CC=1.N1C=CC=CC=1.[C:35](Cl)(=[O:39])[C:36]([CH3:38])=[CH2:37]>C1COCC1>[C:35]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[OH:19])=[CH:8][CH:9]=1)(=[O:39])[C:36]([CH3:38])=[CH2:37]
Reactant: Cc1ccc(O)c(N=Nc2ccc(CCO)cc2)c1
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCc1ccc(N=Nc2cc(C)ccc2O)cc1
Temperature: -20 °C
Reaction time: 20 h

Procedure:
In a 250 ml 3-neck round bottom flask equipped with a magnetic stirrer and gas inlet was dissolved 8.21 g (32.0 mmol) 2-((4-(2-hydroxyethyl)phenyl)diazenyl)-4-methylphenol in 200 ml anhydrous THF. ˜50 mg 4-Methoxyphenol (50 mg, Aldrich) was added followed by 20.1 g (254 mmol) anhydrous pyridine. The reaction mixture was cooled to −20° C. and 4.75 g (45.4 mmol) methacryloyl chloride was added dropwise. The reaction mixture was stirred for 1 hour at −20° C. and 20 hours at ambient temperature. The solid was filtered and 200 ml diethyl ether was added to the filtrate. Ethyl acetate (100 ml) was also added to aid in the separation. The organic layer was washed with 0.5 N HCl, and then dried over magnesium sulfate and then filtered. The solvent was removed under removed pressure and the crude product was recrystallized in ethanol to give an orange solid which was rinsed with cold ethanol and dried overnight under high vacuum at room temperature to afford 3.1 g (30%). 1H NMR (CDCl3) delta: 12.67 (s, 1H, Ar—OH), 7.82 (d, 2H, Ar—H), 7.73 (s, 1H, Ar—H), 7.38 (d, 2H, Ar—H), 7.15 (d, 1H, Ar—H), 6.93 (d, 1H, Ar—H), 6.08 (s, 1H, vinyl-H), 5.56 (s, 1H, vinyl-H), 4.41 (m, 2H, CH2OCO), 3.07 (m, 2H, Ar—CH2), 2.38 (s, 3H, Ar—CH3), 1.93 (s, 3H, C═C—CH3).
Reaction SMILES: [Br-].C(OC([NH:9][C@@H:10]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:11]([O:13][C@@H:14]1[CH:19]2[CH2:20][CH2:21][N+:16]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:17][CH2:18]2)[CH2:15]1)=[O:12])=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41].[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41].[NH2:9][C@@H:10]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:11]([O:13][C@@H:14]1[CH:19]2[CH2:20][CH2:21][N+:16]([CH2:22][CH2:23][O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([CH2:17][CH2:18]2)[CH2:15]1)=[O:12].[NH2:9][C@@H:10]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:11]([O:13][C@@H:14]1[CH:19]2[CH2:20][CH2:21][N+:16]([CH2:22][CH2:23][O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([CH2:17][CH2:18]2)[CH2:15]1)=[O:12]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O[C@H]1C[N+]2(CCOc3ccccc3)CCC1CC2
Agent: [Br-]
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)O[C@H]1C[N+]2(CCOc3ccccc3)CCC1CC2
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a solution of (R)-3-((S)-2-tertbutoxycarbonylamino-phenylpropanoyloxy)-1-(2-phenoxyethyl)-1-azonia-bicyclo[2.2.2]octane bromide (I148) (0.53 mmol) in DCM (5 mL), is added trifluoroacetic acid (0.50 mL, 4.41 mmol) and the mixture stirred at RT overnight. The solvent is evaporated and the resulting crude is purified by preparative LC-MS in order to obtain the title compound as a brown gummy solid (112 mg, 43% overall yield, trifluoroacetate salt and trifluoroacetate anion, single diastereoisomer).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH:7](Br)([CH3:9])[CH3:8]>>[CH:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([CH3:9])[CH3:8]
Reactant: CC(C)Br
Reactant: OCCCCO
Product: CC(C)OCCCCO

Procedure:
Using 1,4- butandiol and isopropylbromide, the above compound is produced.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:23])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH:28]1[C:34]1[N:38]2[CH:39]=[C:40]([O:43][C@H:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C@@H:47]([NH2:54])[CH2:46][CH2:45]3)[CH:41]=[CH:42][C:37]2=[N:36][N:35]=1>>[CH:5]([OH:23])=[O:4].[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:54][C@@H:47]2[C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:44]([O:43][C:40]3[CH:41]=[CH:42][C:37]4[N:38]([C:34]([CH:28]5[CH2:29][N:30]([CH3:33])[CH2:31][CH2:32][N:27]5[CH3:26])=[N:35][N:36]=4)[CH:39]=3)[CH2:45][CH2:46]2)=[O:4])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CN1CCN(C)C(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(C5CN(C)CCN5C)n4c3)c3ccccc32)cc1
Product: O=CO

Procedure:
The title compound was prepared as an off white solid (70 mg, 42%) using (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 107 mg, 0.26 mmol) and Intermediate 86d (104 mg, 0.26 mmol) in a similar manner to Example 1, step d. LCMS (Method 5): Rt 3.64 min, m/z 648 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.83-1.98 (5H, m), 2.05-2.25 (6H, m), 2.30-2.42 (5H, m), 2.75 (2H, d, J 10.7), 2.89-2.94 (1H, m), 3.92-3.95 (1H, m), 4.80-4.86 (1H, m), 5.38-5.46 (1H, m), 6.32 (1H, s), 7.10 (1H, d, J 8.6), 7.26-7.42 (9H, m), 7.75 (1H, d, J 9.7), 8.04 (1H, s), 8.16 (1H, s), 8.46-8.50 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:29])[CH2:15][CH2:16][C:17]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:18]=3[O:19][CH2:20][C:21](O)=[O:22])[C@H:9]([CH3:30])[CH2:8]2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:29])[CH2:15][CH2:16][C:17]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:18]=3[O:19][CH2:20][C:21]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:22])[C@H:9]([CH3:30])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(OCC(=O)O)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(CCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(OCC(=O)NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
To a solution of (2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-3-oxo-propyl}-5-methyl-phenoxy)-acetic acid (0.052 g, 0.12 mmol) in methylene chloride (1 mL) was added 4-dimethylaminopyridine (0.022 g, 0.18 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.032 g, 0.17 mmol), methanesulfonamide (0.015 g, 0.16 mmol) and triethylamine (0.035 mL, 0.25 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 0.2 M aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by trituration in methylene chloride/diethyl ether/hexanes to give the title compound (0.050 g, LRMS: 520.3).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[F:15])C.Cl>CC(C)=O>[F:15][C:6]1[CH:7]=[C:8]([C:11]([OH:14])([CH3:12])[CH3:13])[CH:9]=[CH:10][C:5]=1[CH:4]=[O:3]
Reactant: CCOC(OCC)c1ccc(C(C)(C)O)cc1F
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)(O)c1ccc(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-[4-(diethoxymethyl)-3-fluorophenyl]propan-2-ol (25.6 g, 100 mmol) in acetone (50 mL) was added dropwise to aqueous HCl (6M, 50 mL) cooled with ice-water to keep the internal temperature less than 10° C. After addition, the mixture was stirred at room temperature for 6 hrs. The mixture was extracted twice with ethyl acetate. The combined organics were washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 10.23 (s, 1H), 7.81 (d, 1H), 7.34 (d, 1H), 7.30 (d, 1H), 2.01 (s, 1H), 1.49 (s, 61-1).