Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:12]=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][CH2:15][CH2:14][N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:10][CH:9]=1)[CH:12]=[O:13]
Reactant: COC(=O)C(=O)c1ccc(N(C=O)CCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=CN(CCOc1ccc2ccccc2c1)c1ccc(C(=O)C(=O)O)cc1
Yield: 83.1 %

Procedure:
A solution of 4-[N-[2-(2-naphthalenyloxy)ethyl]formamido]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in hot methanol (5 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (3.0 mL) and the mixture was concentrated to remove the organic solvents. The residue, in water, was treated with 2N hydrochloric acid and the mixture was chilled, filtered, and washed with water. The solids were dissolved in a mixture of tetrahydrofuran and dichloromethane, dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.4 g of purified 4-[N-[2-(2-naphthalenyloxy)ethyl]formamido]-alpha-oxobenzeneacetic acid as a yellow solid, mp 172° C. with decomposition.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(C(C)C)CC)(C)C.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl>CS(C)=O.O>[I:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: NCc1cccc(I)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CNCc1cccc(I)c1
Reaction time: 2 h

Procedure:
3-Iodobenzylamine hydrochloride (1.0 g) and diisopropylethylamine (1.29 ml) were taken up in dry dimethylsulfoxide (60 ml) and treated with ethyl bromoacetate and stirred under nitrogen for 2 h. 2M HCl (1.85 ml) and water (250 ml) were added. This was extracted with EtOAc, the aqueous phase was taken to pH 8 and extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (Biotage, 40 g) eluting with EtOAc-cyclohexane-diisopropylethylamine (10:89:1 then 20:79:1) to give the title compound (0.571 g) LCMS RT 2.02 min.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH3:34][C:35]([CH3:37])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)Cl>[CH:35]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)([CH3:37])[CH3:34]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
A suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (215 mg, 0.45 mmol) in dry DCE (4.5 mL) under argon was treated with acetone (49 μL, 0.67 mmol) followed by sodium triacetoxyborohydride (190 mg, 0.89 mmol). The reaction mixture was stirred at RT for 18 hours. Aqueous saturated sodium bicarbonate solution and DCM were added and the phases were separated. The aqueous phase was extracted with DCM (×2) and the combined organic phase was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant solid was triturated with ether, to give 423 as an off-white solid (115 mg, 63%). LCMS: RT=7.44 min, [M+H]+=410. 1 H NMR δ (ppm) (CDCl3): 8.30 (1H, d, J=8.17 Hz), 7.89 (1 H, s), 7.07 (1 H, dd, J=8.20, 1.83 Hz), 6.96 (1 H, d, J=1.81 Hz), 5.93-5.84 (1 H, m), 4.38 (2 H, t, J=5.05 Hz), 3.79 (2 H, t, J=7.00 Hz), 3.74-3.63 (1 H, m), 3.39 (2 H, t, J=5.06 Hz), 3.12 (2 H, m), 2.38 (1 H, m), 1.60 (6 H, d, J=6.63 Hz), 0.97 (6 H, d, J=6.21 Hz)
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[OH:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:63]([CH2:65][CH2:66][O:67][CH2:68]Cl)#[N:64].C(=O)(O)[O-].[Na+]>ClCCCl>[O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[O:21][CH2:68][O:67][CH2:66][CH2:65][C:63]#[N:64])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCOCCl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
N2-Phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)guanosine (720 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added, and 365 mg of dibutylstannyl dichloride (1.2 mmol) was added subsequently. Then, the reaction was performed at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethyl ether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was mixed with an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N2-phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxy methyl)guanosine (384 mg, yield 48%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1
Reactant: Cc1ccccc1N
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 10.8 g (101 mmol) of 2-methylaniline, 23.3 g (67.0 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 3), and 10.2 g (74.0 mmol) of K2CO3 in 450 mL of DMF was stirred for 12 h at 80° C. The resulting mixture was poured into 1000 mL of water. The product was extracted with 3×200 ml of ethyl acetate. The combined extract was dried over MgSO4 and then evaporated to dryness. The residue was re-crystallized from a mixture of 200 ml of hexane and 10 ml of ethyl acetate. Yield 15.7 g (63%) of a brown crystalline powder. Anal. calc. for C24H28BNO2: C, 77.22; H, 7.56; N, 3.75. Found: C, 77.33; H, 7.67; N, 3.59. 1H NMR (CDCl3): δ 8.20 (m, 1H, 8-H in naphthyl), 7.84 (d, J=8.5 Hz, 1H, 4-H in naphthyl), 7.82 (m, 1H, 5-H in naphthyl), 7.43-7.52 (m, 3H, 3,6,7-H in naphthyl), 7.14 (m, 1H, 5-H in o-tolyl), 7.06 (m, 1H, 3-H in o-tolyl), 6.79 (m, 1H, 6-H in o-tolyl), 6.68 (m, 1H, 4-H in o-tolyl), 4.53 (s, 2H, CH2N), 3.95 (br.s, 1H, NH), 2.11 (s, 3H, 2-Me in o-tolyl), 1.36 (s, 12H, CMe2CMe2).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.OCCOC1N=CN=C([NH:34][S:35]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:37])=[O:36])C=1C1C=CC(C)=CC=1>>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=[C:2]([NH:34][S:35]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:36])=[O:37])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCO)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)CCc1ccccc1

Procedure:
2-Phenylethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-amide was prepared in analogy to Referential Example 7 from 4,6-dichloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine (prepared as disclosed in [6]) and 2-phenylethane sulfonamide potassium salt (Referential Example 1). LC-MS: tR=4.85 min, [M+1]+=498.38, [M−1]−=496.19.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[CH3:17][C:18]1([CH3:25])[CH2:21][CH:20]([C:22](Cl)=[O:23])[CH2:19]1>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:22]([CH:20]2[CH2:21][C:18]([CH3:25])([CH3:17])[CH2:19]2)=[O:23])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC1(C)CC(C(=O)Cl)C1
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)C2CC(C)(C)C2)c(O)c1

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 3,3-dimethylcyclobutanecarbonyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)- alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Br[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.BrCC1C=CC=C(F)C=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: Fc1cccc(CBr)c1
Product: N#Cc1ccc(COc2cccc(N)c2)cc1

Procedure:
3-Nitro-phenol was reacted with 4-bromomethyl-benzonitrile according to the procedure from Example 199A substituting 4-bromomethyl-benzonitrile for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:13]([C:14](OCC)=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH3:27])([CH3:26])[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(Cl)Cl.CCCCCC>C1COCC1>[CH:1]([C:4]1[C:13]([CH2:14][OH:15])=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH3:27])([CH3:26])[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CCCC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1CO)CCCC2(C)C
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To the intermediate obtained in Step B (1.32 g, 3.6 mmol) in THF (35 mL) was added lithium aluminum hydride (1 M/THF, 2 eq., 7.2 mL) dropwise. The reaction was refluxed for 1.5 hours and cooled to room temperature. Then the reaction was quenched with water and the THF was evaporated. The residue was partitioned between diethyl ether (150 mL) and water (100 mL). The organic layer was washed with brine (1×100 mL), dried with MgSO4, filtered, and concentrated to afford a solid. Flash chromatography (40% CH2Cl2/hexane) afforded the title compound as a white solid (808 mg, 2.5 mmol, 70%). 1H NMR (300 MHz, CDCl3): δ 7.13 (d, J=7.0 Hz, 4H), 4.36 (d, J=5.5 Hz, 2H), 3.42 (septet, J=6.6 Hz, 1H), 2.24 (t, J=5.5 Hz, 2H), 1.67 (m, 4H), 1.32 (m, 13H). FAB-MS: calculated for (C21H26FNO) 327, found 328 (M+H). mp 146-149° C. Rf=0.2 (50% CH2Cl2/hexane).
Reaction SMILES: FC(F)(F)C(O)=O.C([CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]1[C:26]([NH:27][CH:28]([CH3:30])[CH3:29])=[CH:25][CH:24]=[CH:23][N:22]=1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].O>ClCCl>[N:16]1([C:21]2[C:26]([NH:27][CH:28]([CH3:30])[CH3:29])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:15][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CC(C)Nc1cccnc1N1CCNCC1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N1CCNCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (2.0 mL) was added to a stirred solution of 2-(Boc-piperazinyl)-3-(i-propylamino)pyridine 4 (1.426 g, 4.45 mmol) in dichloromethane (10 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min, at room temperature for 1 h 15 min. Additional quantities of TFA (2.0 mL) were added. The mixture was stirred at room temperature for another 23 h. Sat. K2CO3 solution was slowly added to quench the reaction (gas ↑). Small amount of water was added to help the layers separation. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×25 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the product in quantitative yield. 1H-NMR (CDCl3): 7.681 (dd, J=5.0 Hz and 1.5 Hz, 1H, Ar—H), 6.890 (dd, J=8.0 Hz and 5.0 Hz, 1H, Ar—H), 6.800 (dd, J=8.0 Hz and 1.5 Hz, 1H, Ar—H), 4.170 (d, J=7.5 Hz, 1H, NH), 3.567-3.485 (m, 1H, CH), 3.046 (s, 8H, 4 CH2), 1.983 (br, 1H, NH), 1.234 (d, J=6.0 Hz, 6H, 2 CH3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:11](=O)[CH2:12][CH3:13])=[C:6]([S:9][CH3:10])SC)[CH3:2].Cl.[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([NH:25][NH2:26])=[C:20]([CH3:27])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:11]([CH2:12][CH3:13])=[N:26][N:25]([C:21]2[C:20]([CH3:27])=[CH:19][C:18]([Br:17])=[CH:23][C:22]=2[CH3:24])[C:6]=1[S:9][CH3:10])=[O:15])[CH3:2]
Reactant: CCOC(=O)C(C(=O)CC)=C(SC)SC
Reactant: Cc1cc(Br)cc(C)c1NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(CC)nn(-c2c(C)cc(Br)cc2C)c1SC
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 8.58 g (34.5 mmol) of 3,3-bismethylthio-2-propionylacrylic acid ethyl ester, 8.67 g (34.5 mmol) of 4-bromo-2,6-dimethylphenylhydrazine hydrochloride and 7.31 g (69.0 mmol) of sodium carbonate in 150 mL of ethanol in a 250 mL RBF under an atmosphere of dry N2 was refluxed over the weekend. The reaction mixture was cooled to room temperature and evaporated to a reddish solid. This material was partitioned between 150 mL of water and 200 mL of methylene chloride (CH2Cl2). The organic layer was separated, dried over sodium sulfate and evaporated to a gum which was chromatographed on a silica gel column eluting with CH2Cl2 to give 2.6 g of pure product as a yellow oil. 1H-NMR (CDCl3) δ 1.26 (3H, t, J=7), 1.40 (3H, t, J=7), 1.94 (6H, s), 2.33 (3H, s), 2.93 (2H, q, J=7), 4.36 (2H, q, J=7), 7.30 (2H, s).
Reaction SMILES: C(#N)C.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:10][C:11]([F:21])([F:20])[S:12]([O:15][Si](C)(C)C)(=[O:14])=[O:13].[F:22]F>CCOCC>[F:10][C:11]([F:21])([F:20])[S:12]([O-:15])(=[O:14])=[O:13].[F:22][N+:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccncc1
Reactant: FF
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: F[n+]1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Yield: 78 %

Procedure:
To a 5 ml anhydrous acetonitrile solution containing 0.408 g (5.17 mmoles) of pyridine, 1.0 ml (5.17 mmoles) of trimethylsilyl trifluoromethanesulfonate as the XM reactant was added at -40° C. under stirring. To the resultant solution a mixed gas of fluorine and nitrogen (1:9), 10 minutes after the addition, was introduced at a rate of 15 ml/min. The amount of fluorine gas introduced was 15.5 mmoles. After the completion of the reaction, an amount of ether cooled to -60° C. was added to the solution to precipitate crystals which were filtered to give 0.99 g (yield: 78%) of N-fluoropyridinium trifluoromethanesulfonate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].O1CCOCC1.[CH3:39][NH2:40]>C(Cl)Cl.CN(C=O)C>[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:40][CH3:39])=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12]
Reactant: CN
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)cc1
Temperature: 25 °C
Yield: 49 %

Procedure:
Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringe wise to (−)-4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoic acid (300 mg, 0.79 mmol, prepared in example 1a) in methylene chloride (15 mL) while stirring under nitrogen at room temperature. Immediately, 1 drop of DMF was added by pipette initiating a foaming of the mixture. The reaction was stirred one hour at this temperature and then concentrated under reduced vacuum to yield a white semi-solid. This material was placed into dioxane (20 mL) and added dropwise to a stirring solution of 40% methylamine (5 mL) at room temperature and the mixture was stirred overnight. In the morning, the solution was concentrated under reduced vacuum and the resulting oil was taken into methylene chloride and the organic layer was washed once with H2O, dried over K2CO3, filtered, and concentrated under reduced vacuum to yield 391 mg as a solid. This material was purified via recrystallization from hexane/ethyl acetate 1:1 to yield the title compound (231 mg, 49%) as a white solid. Ion spray M.S. 391.4 (M*−1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:4][C:3]1([CH3:16])[CH3:15].[C:17]([O:21][C:22](NC(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([NH:1][CH:2]1[CH2:6][N:5]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:4][C:3]1([CH3:15])[CH3:16])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C[C@H](c1ccccc1)N1CC(N)C(C)(C)C1
Reactant: CC(C)(C)OC(=O)NC(C#N)c1ccccc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(NC(=O)OC(C)(C)C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To an ice cooled solution of 3.69 g of 4-amino-3,3-dimethyl-1-[1-(R)-phenylethyl]-pyrrolidine in 40 ml of anhydrous tetrahydrofuran there was added 4.92 g of 2-(tert-butoxycarbonylamino)-2-phenylacetonitrile and the mixture was stirred at room temperature for 1 hr. Solvent was removed under reduced pressure, and to the residue there was added ethyl acetate. The mixture was washed with a 1N sodium hydroxide aqueous solution three times and then dried. Solvent wa then removed under reduced pressure. The residue was purified through column chromatography using 200 g of silica gel in a column with chloroform as the eluant containing from 1% to 5% methanol to yield 4.32 g of the titled compound. 1H-NMR(CDCl3) δ ppm;1.00, 16(each 3H, s), 1.40(3H, d, J=7.2 Hz), 1.52(9H, s), 2.00-3.62(5H, m), 3.85-4.10(1H, m), 4.90(1H, bs), 7.38(5H, s)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[CH2:17][I:18])([O-:13])=[O:12].CCOCC>CC(C)=O>[I-:18].[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[CH2:17][N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1])([O-:13])=[O:12]
Reactant: Cc1nc2ccccc2s1
Reactant: O=[N+]([O-])c1cc(CI)cc([N+](=O)[O-])c1
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cc1sc2ccccc2[n+]1Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: [I-]
Yield: 54.2 %

Procedure:
2-methylbenzothiazole (3 ml, 20.1 mmol) was dissolved in acetone (25 ml), to which was added 3,5-dinitrobenzyl iodide (7.4 g, 24.1 mmol) and heated with stirring to reflux for 15 hours. The reaction was allowed to cool and added drop-wise to ether (500 ml) to produce a fine yellow solid which was filtered and dried to constant weight in vacuo to give 3-(3,5-dinitrobenzyl)-2-methyl-1,3-benzothiazol-3-ium iodide (5 g, 10.9 mmol, 45% yield). MS: m/z=328 (C15H12N3O4S=330.3). 1H NMR (200 MHz-DMSO-d6): δ 2.85 (s, 1 H); 3.7 (s, 3H); 6.35 (s, 2H); 7.37 (m, 2H); 8.23 (d, 1H); 8.53 (d, 1H); 8.62 (s, 2H): 8.8 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][Cl:38]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:35][CH2:36][CH2:37][Cl:38])[CH2:15][CH2:16]2)[CH:8]=[C:7]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C2(C)CC2)n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(N2CCN(CCCCl)CC2)cc(C2(C)CC2)n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
7 g of 2-tert-butyl-4-piperazin-1-yl-6-(1-methylcyclopropyl)-pyrimidine (25.5 mmol; prepared by analogy to steps a.2.1 to a.2.4 starting from 1-methylcyclopropyl carbonic acid chloride) were dissolved in 50 ml of dimethyl formamide. 2.58 of triethylamine (25.5 mmol), and 3.53 g of potassium carbonate were added, followed by dropwise addition of 4.62 g of 1-bromo-3-chloropropane. After stirring for 1.5 h at 50° C. the reaction mixture was stirred overnight at room temperature. The precipitate was filtered off and washed with dimethylformamide. The filtrate was partitioned between 150 ml of ethyl acetate and 50 ml of water. The organic layer was separated and the aqueous layer was extracted with 30 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (ethyl acetate) to yield 4.6 g of the title compound.