Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[CH:10](O)([CH3:12])[CH3:11].Cl.COC(OC)(C)C=O>O>[CH3:11]/[C:10](/[CH:12]=[N:5]/[N:6]=[C:7]([NH2:9])[NH2:8])=[N:5]\[N:6]=[C:7]([NH2:9])[NH2:8]
Reactant: CC(C)O
Reactant: N=C(N)NN
Agent: COC(C)(C=O)OC
Agent: Cl
Agent: O=C(O)O
Solvent: O
Product: CC(/C=N/N=C(N)N)=N\N=C(N)N
Temperature: 32 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
Aminoguanidine bicarbonate (Aldrich 98.5%) was slurried in DI water at 35°-40° C. for about 30 minutes, the suspension was filtered to remove diaminoguanidine and other impurities amounting to about 1% w/w. 505 g, 3.8 mol of the filtered aminoguanidine bicarbonate was suspended in 200 g DI water and 300 g (156 mL) isopropanol to give a heavy, but stirrable mixture. Concentrated HCl (376 g, 37.8%) was cautiously added dropwise over a 1.5 hr period to prevent excessive foaming (Note 1). The mixture stirred readily after 5% of the HCl had been added. The reaction was endothermic and the temperature was maintained at between 19° C. and 28° C. At the end of the addition a clear colorless solution was obtained (Note 2). It was warmed to 32° C. and stirred for 20 minutes (Note 3). The methyl glyoxal dimethylacetal (212 g, 1.79 mol) (Fluka, 98%) was next added over 1.5 hours at a temperature of 30°-35° ) (Note 4). The suspension was stirred overnight at ambient temperature. The next morning isopropanol (2.0 kg) was added over 15-20 minutes. The suspension was cooled to about 10° C. and stirring was continued for 1.5 hours. The solids were collected by filtration and rinsed with 2×200 mL isopropanol. After drying overnight in a vacuum oven at 30°-35° C., 463 g (47%) of the crude MGBG was obtained. TLC [acetone 90, water 5, NH4OH 5]; HPLC (ETI~0.79%); nmr (dmsod6).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.CCN(CC)CC.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:9][CH2:8][CH:5]2[CH2:6][O:7][C:2]([CH3:10])([CH3:1])[O:3][CH2:4]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)OC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 1.5 g (10.26 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl)methanol and 1.71 mL of Et3N in 15 mL of DCM, cooled to 0° C., are added 2.15 g (11.3 mmol) of tosyl chloride. The medium is allowed to warm to room temperature, and stirring is continued for 1 hour. The medium is taken up in 100 mL of DCM, washed successively with 0.11N HCl (2×20 mL) and brine (20 mL), dried over Na2SO4, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 3 g of (2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate are obtained in the form of a colourless oil.
Reaction SMILES: [CH2:1]([C@@H:7]([C@@H:18]([OH:39])[CH2:19][C@H:20]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C1COCC1.[Pd]>[CH2:1]([C@@H:7]([C@@H:18]([OH:39])[CH2:19][C@H:20]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCC[C@H](C[C@H](O)[C@H](CCCCCC)C(=O)OCc1ccccc1)OC1CCCCO1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@H](C[C@H](O)[C@H](CCCCCC)C(=O)O)OC1CCCCO1
Reaction time: 3 h

Procedure:
(M)(h) 430 mg of benzyl (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate in 10 ml of THF were treated with Pd/C 10% and hydrogenated for 3 hours. The catalyst was filtered off and, after evaporation of the filtrate, the product was chromatographed on silica gel. There was obtained (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoic acid.
Reaction SMILES: [Cl:1]/[C:2](/[C:9]([O:11][CH3:12])=[O:10])=[C:3](\Cl)/[C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:17]>CN(C)C=O>[NH2:17]/[C:3](/[C:4]([O:6][CH3:7])=[O:5])=[C:2](\[Cl:1])/[C:9]([O:11][CH3:12])=[O:10]
Reactant: [NH4+]
Reactant: COC(=O)/C(Cl)=C(/Cl)C(=O)OC
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)/C(N)=C(/Cl)C(=O)OC
Temperature: 120 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
53.25 g (0.25 mol) of dimethyl dichloromaleate were dissolved in 100 ml of dimethylformamide, and 48.16 g (0.625 mol) of ammonium acetate were added. The mixture was rapidly heated to 120° C. and stirred at 110° C. to 120° C. for one hour. The solvent was subsequently removed by distillation, the residue was taken up in methylene chloride, and the solution was washed with water. The methylene chloride was removed by distillation on an evaporator, and, after, recrystallization 40 g (83% yield) of dimethyl aminochloromaleate were obtained in the form of yellowish, cubic crystals (m.p. 96°-98° C.)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:40][O:41][C:42]1[C:43]([CH3:70])=[C:44]([C:61]([O:68][CH3:69])=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[CH2:45][C:46]1[CH:47]=[CH:48][C:49](O)=[C:50]([CH:59]=1)[C:51]([N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)=[O:52].[OH-].[Na+]>C1C=CC=CC=1>[CH3:40][O:41][C:42]1[C:43]([CH3:70])=[C:44]([C:61]([O:68][CH3:69])=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[CH2:45][C:46]1[CH:47]=[CH:48][C:49]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:50]([CH:59]=1)[C:51]([N:53]1[CH2:54][CH2:55][O:56][CH2:57][CH2:58]1)=[O:52]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Reactant: OCc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1c(C)c(Cc2ccc(OCc3cccnc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
3-Pyridinemethanol (0.080 g, 0.731 mmol), triphenylphosphine (0.192 g, 0.731 mmol) and diethylazodicarboxylate (0.127 g, 0.731 mmol) were added to a benzene solution of N-[5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]morpholine (0.210 g, 0.487 mmol) and the solution was stirred at room temperature for 12 hours. The reaction solution was poured into an aqueous 2N sodium hydroxide solution (15 ml) and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1.5:8.5) to obtain the titled compound (0.195 g, 0.374 mmol, 77%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1.C(=O)(O)[O-].[Na+].C(Cl)Cl>C1C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Clc1ccn2ccnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: ClCCl
Product: c1ccc(-c2nn3c(c2-c2ccn4ccnc4c2)CCC3)nc1
Temperature: 100 °C
Yield: 15.5 %

Procedure:
Combine 7-chloro-imidazo[1,2-a]pyridine (PCT Appl. WO 01/38326 A2; 134 mg, 0.88 mmol) with 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 369 mg, 0.97 mmol) in the presence of tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol) and 2M aqueous sodium bicarbonate (1.0 mL) in benzene (2.1 mL) and ethanol (0.3 mL). Heat the mixture for 67 h at 100° C. Dilute the reaction with methylene chloride (10 mL) and water (10 mL). Separate the layers and extract the aqueous layer with methylene chloride (2×10 mL). Combine the organic layers and dry over sodium sulfate. Filter the solution and evaporate the solvent. Purify the crude product by flash chromatography using the appropriate ammonia in methanol/methylene chloride mixture to give the title compound as a tan solid (41 mg, 15%). MS m/e (302.0, M+1). 1H NMR (CDCl3) δ 8.57 (m, 1H), 7.96 (dd, J=1, 7 Hz, 1H), 7.6 (m, 5H), 7.19 (m, 1H), 6.69 (dd, J=1, 7 Hz, 1H), 4.27 (t, J=8 Hz, 2H), 3.08(t, J=7 Hz, 2H), 2.71 (q, J=7 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].C([O:8][C:9](=[O:46])[C:10]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[F:45])([CH3:37])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH:21]2[CH2:25][N:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30](OC)=[CH:29][CH:28]=3)[C:23](=[O:35])[N:22]2[CH3:36])=[CH:14][CH:13]=1)C.[Cs+].C(OC(=O)C(OC1C=CC=CC=1F)(C)CC1C=CC(O)=CC=1)C.COC1C=CC(CN2CC(CCOS(C3C=CC(C)=CC=3)(=O)=O)N(C)C2=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH2:26]([N:24]1[CH2:25][CH:21]([CH2:20][CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][C:10]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[F:45])([CH3:37])[C:9]([OH:46])=[O:8])=[CH:13][CH:14]=2)[N:22]([CH3:36])[C:23]1=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)Oc1ccccc1F
Agent: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Agent: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)N(Cc2ccccc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1
Yield: 35777556 %

Procedure:
2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester Cesium carbonate (6.12 g, 18.76 nmol) is added to a solution of 2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester 1.99 g, 6.26 mmol) and toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (2.88 g, 6.88 mmol) in DMF (20 mL). The resultant mixture is stirred at 65° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed with 1N HCl, water, and brine. The organic layer is dried over MgSO4, concentrated in vacuo, and purified by flash column chromatography (17% acetone in hexanes) to provide the title compound (3.4 g, 97%). 1H NMR (400 MHz, CDCl3): δ 7.19 (d, 2H, J=5.4 Hz), 7.17 (d, 2H, J=5.4 Hz), 7.07-7.01 (m, 1H), 6.97-6.87 (m, 3H), 6.83 (d, 2H, J=8.6 Hz), 6.74 (d, 2H, J=8.6 Hz), 4.32, 4.28 (ABq, 2H, J=14.6 Hz), 4.20 (q, 2H, J=7.5 Hz), 3.94 (t, 2H, J=5.9 Hz), 3.77 (s, 3H), 3.60-3.53 (m, 1H), 3.33 (t, 1H, J=8.6 Hz), 3.26, 3.14 (ABq, 2H, J=14.0 Hz), 2.92 (t, 1 h, J=8.6 Hz), 2.82 (s, 3H), 2.24-2.17 (m, 1H), 1.89-1.82 (m, 1H), 1.38 (s, 3H), 1.23 (t, 3H, J=7.5 Hz). MS [EI+] 565 (M+H)+. Rf=0.48 in 50% acetone in hexanes.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[O:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][N:45]=1)[C:38]#[N:39]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]1([C:41]2[CH:40]=[C:37]([CH:36]=[CH:35][C:42]=2[O:43][C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][N:45]=2)[C:38]#[N:39])[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(Br)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C2CC2)c1
Temperature: 80 °C
Yield: 90.2 %

Procedure:
In a vial 3-bromo-4-[(5-nitro-2-pyridinyl)oxy]benzonitrile (Intermediate 122, 800 mg) was dissolved in 16.0 mL of toluene. Cyclopropylboronic acid (1073.8 mg, 12.5 mmol) was added, followed by Pd(OAc)2 (56.1 mg, 0.25 mmol) and (Cy)3P (70.0 mg 0.25 mmol). Then, an aqueous solution (8.0 mL of water) of K3PO4 (1855.0 mg, 8.75 mmol) was added. The reaction mixture was heated at 80° C. overnight. After cooling down to r.t., the mixture was partitioned between brine and EtOAc and the separated aqueous phase was extracted with EtOAc (three times). The collected organic were dried over Na2SO4, filtered and evaporated. The crude obtained was charged on a silica gel column and eluted with Cyclohexane/EtOAc (from 100:0 to 80:20 Cyclohexane/EtOAc) affording 634 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[C:7]([OH:18])=[CH:8][CH:9]=[C:10]([Cl:17])[C:11]=1[NH:12]2)(=[O:3])[NH2:2].[H-].[Na+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Cl-].[NH4+]>O1CCCC1>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:18][C:7]1[C:6]2[C:5]3[C:13](=[CH:14][CH:15]=[CH:16][C:4]=3[C:1](=[O:3])[NH2:2])[NH:12][C:11]=2[C:10]([Cl:17])=[CH:9][CH:8]=1
Reactant: NC(=O)c1cccc2[nH]c3c(Cl)ccc(O)c3c12
Reactant: COC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(Cl)c2[nH]c3cccc(C(N)=O)c3c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 0.28 g of 5-carbamoyl-4-hydroxy-1-chlorocarbazole in 6 ml of tetrahydrofuran was added to 0.043 g of sodium hydride (60% in mineral oil) in 1 ml of tetrahydrofuran and stirred for 60 minutes at room temperature. Methyl bromoacetate (0.11 ml) was then added and the reaction was stirred overnight. The reaction mixture was poured into 20 ml of saturated ammonium chloride solution and then extracted twice with ethyl acetate. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with chloroform and then 2:1 chloroform/ethyl acetate to afford 0.16 g (45%) of the subtitle compound. ESIMS m/e 333 (M++1), 335 (M++3), 331 (M+−1) NMR (300 MHz, d6-DMSO): δ 11.73 (s, 1H); 7.56 (d, J=8.1, 1H); 7.50 (br s, 1H); 7.43-7.35 (m, 2H); 7.18 (br s, 1H); 7.06 (d, J=7.8, 1H); 6.56 (d, J=8.6, 1H); 4.90 (s, 2H); 3.70 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6].O.C(N(CC)CC)C.[CH3:16][C:17]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])[CH3:18]>O1CCOCC1.CCCCCC>[C:17]([O:20][C:21]([N:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6])=[O:22])([CH3:19])([CH3:18])[CH3:16]
Reactant: O=C(O)[C@@H]1CCN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reaction time: 6.75 h

Procedure:
(S)-(−)-2-Azetidinecarboxylic acid (Aldrich Chemical Company, Milwaukee, Wis.) (1.00 g, 9.89 mmol) is dissolved in 12 mL of 1:1 dioxane:water. Triethylamine (2.1 mL, 14.84 mmol) is added followed by BOC-ON (2.68 g, 10.9 mmol). The mixture is stirred for 6.75 hours then poured onto water (50 mL) and extracted with ether (7 times, 50 mL each). The aqueous solution is cooled in an ice-bath and the pH adjusted to approximately 2.5 with ice-cold 1N HCl solution. The resulting solution is extracted with methylene chloride (3 times, 50 mL each). The combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to afford an oil. Hexane (100 mL) is added to this oil and the mixture placed in the freezer overnight. The hexane is decanted and the product (1) dried under vacuum to afford a white solid. ISMS: MH+ 202.2
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([CH3:19])[CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:18][CH2:17][C@H:16]([CH3:19])[CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)CN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (R)-(-)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanol (7.26 gm, 24.8 mmoles), triethylamine (3 ml, 30 mmoles) in methylene chloride (DCM, 120 ml), methanesulfonyl chloride (3.13 gm, 27.3 mmoles) was added dropwise at 0° C. The mixture was stirred at room temperature for 1 hr., then concentrated down to a crude mixture. Triethylamine hydrochloride salt was removed by filtration with DCM/ether as solvent. The crude oily mixture was purified with a flash chromatography column (SiO2, 90 gm; eluted with DCM). The colorless oil, which is the methanesulfonate ester, weighed 6.48 (70%), and was used directly in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:22]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:22])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of diethyl 2-(4-bromophenyl)malonate (1.5 g, 4.8 mmol) in dry THF (5 mL) at 0° C. was added sodium hydride (380 mg, 9.5 mmol). After stirring for 30 minutes at 0° C., iodomethane (600 μL, 9.5 mmol) was added and the reaction was allowed to warm to room temperature. After stirring for 12 h at room temperature, the reaction was quenched with water (3 mL). The mixture was partitioned between 1 N HCl (10 mL) and dichloromethane (10 mL), and the organic layer was separated. The organic layer was washed with 1 N HCl (10 mL), dried over Na2SO4 and evaporated. The crude material was purified by silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes, to give diethyl 2-(4-bromophenyl)-2-methylmalonate (850 mg, 55%) 1H NMR (400 MHz, DMSO-d6) δ7.59-7.55 (m, 2H), 7.31-7.27 (m, 2H), 4.21-4.14 (m, 4H), 1.75 (s, 3H), 1.19-1.16 (m, 6H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=2[OH:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[Br:21]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.[Fe]>[Br:21][C:9]1[C:8]([OH:15])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: O=Cc1ccc(OC2CCCC2)c(O)c1
Reactant: BrBr
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Solvent: CC(=O)O
Product: O=Cc1ccc(OC2CCCC2)c(O)c1Br
Temperature: 15 °C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
4-cyclopentoxy-3-hydroxy-benzaldehyde (1.0 gm, 4.84 mmol) was dissolved in glacial acetic acid (20 ml). Anhydrous sodium acetate (0.8 gm, 9.7 mmol) was added to the above solution followed by powdered iron (0.022 gm). The system was flushed thoroughly with nitrogen. A solution of bromine (0.854 gm, 5.32 mmol) in glacial acetic acid (10 ml) was added to the above stirred suspension at 15° C. over a period of 15 min. The reaction mixture was stirred at 15° C. for 45 min. The reaction mixture was poured into aqueous 2% sodium bisulfite (100 ml) and stirred for 10 min. The precipitate was filtered washed with water (100 ml), and dried to obtain 800 mg of 2-bromo-4-cyclopentoxy-3-hydroxy-benzaldehyde as white powder mp: 107-109° C.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(C(F)(F)C(F)C(F)(F)F)CC)C.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:34][C:11]([C:1]23[CH2:2][CH:3]4[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]4)[CH2:8]2)[CH2:10]3)=[O:13])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCCC1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: CCN(CC)C(F)(F)C(F)C(F)(F)F
Product: O=C(NC1CCCCC1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
1-Adamantanecarboxylic acid (10.8 g, 0.06 mole) was dissolved in N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (13.4 g, 0.06 mole) as described in example 1. After the reaction mixture cooled to room temperature, cyclohexylamine (14.88 g, 17.2 ml, 0.15 mole) was added slowly and a heavy precipitate of the amide appeared almost immediately. The N-cyclohexyl-1-adamantanecarboxamide was isolated as described in example 1 to give 14.8 g, 94.4%; mp 199.3-200.4° C. The analytical sample was recrystallized from cyclohexane and sublimed. Anal. Calcd. for C17H27NO: C, 78.18; H. 10.34; N, 5.36. Found: C, 77.97; H, 10.46; N, 5.32.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[OH-].[Na+].[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>C(Cl)Cl.C(Cl)Cl.O.O>[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:2]2[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(O)C1CNC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)C1CN(S(=O)(=O)c2ccc(I)cc2)C1
Yield: 43.8 %

Procedure:
To a stirred solution of azetidine-3-carboxylic acid hydrochloride (1.0 g, 7.27 mmol) in DCM (25 mL) is added 5N aqueous NaOH (10 mL) and water (10 mL). p-Iodobenzenesulfonyl chloride (2.41 g, 7.98 mmol) is added portionwise. After 18 h the reaction mixture is diluted with DCM/water. The basic aqueous layer is acidified with 5N aqueous HCl. The resultant precipitate is filtered, washed with water and MeCN. Drying in air gives 1.17 g (44%) of 1-[(4-iodophenyl)sulfonyl]azetidine-3-carboxylic acid. m/z=368 [M++H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]1)[C:5]([OH:7])=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:26]2)=[CH:21][CH:20]=1>>[CH3:31][N:30]([CH3:32])[CH:27]1[CH2:28][CH2:29][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]4)=[C:2]([F:1])[CH:3]=3)=[CH:20][CH:21]=2)[CH2:26]1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: CC1CCN(c2ccc(C(=O)O)cc2F)CC1
Product: CC1CCN(c2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)cc2F)CC1

Procedure:
3-Fluoro-4-(4-methylpiperidin-1-yl)benzoic acid was reacted with [1-(4-aminophenyl)-pyrrolidin-3-yl]dimethylamine by method E-a. This resulted in the product with the molecular weight of 424.00 (C25H33FN4O); MS (ESI): 425 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([OH:22])=[O:21])[CH2:3]1.[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([O:22][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)=[O:21])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 89.8 %

Procedure:
(2S,4R)-4-Hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-2-carboxylic acid (930 mg, 3 mmol), 4-nitrobenzylbromide (660 mg, 3.05 mmol) and potassium carbonate (209 mg, 1.51 mmol) were stirred together in N,N-dimethylformamide (lOml) for 3.5 h. The mixture was poured into water (100 ml)/ethyl acetate (100 ml) and the layers separated. The aqueous layer was re-extracted with ethyl acetate (50 ml). The combined organic layers were washed with water (50 ml),×4), brine (20 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with ethyl acetate hexane mixture, followed by ethyl acetate to give the title compound (1.20 g, 90%) as a mixture of conformers/rotamers; νmax (CH2Cl2) 3610, 3470, 2960, 1735, 1710, 1610, 1535, and 1350 cm-1 ; δH (400 MHz, CDCl3) 1.90 (1H, broad d, J ca 7.4 Hz), 2.05-2.20 (1H, m), 2.3-2.5 (1H, m), 3.6-3.8 (2H, m), 4.58 (1H, broad d, J ca 9.3 Hz), 4.63 (1H, approx dt J 1.9, 8.1 Hz), 5.05-5.35 (4H, m,) 7.30-7.50 (4H, m), and 8.1-8.2 (4H, m); [Mass spectrum: M+ (445)].