Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([S:8][C:9]([Cl:12])([Cl:11])[F:10])[CH:5]=[N:4]1.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:11][C:9]([Cl:12])([F:10])[S:8][C:6]1[CH:5]=[N:4][N:3]([CH2:2][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[CH:7]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(Cl)(Cl)Sc1cnn(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(SC(F)(Cl)Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
0.21 g of 1-(chloromethyl)-4-[(dichlorofluoromethyl)thio]-1H-pyrazole and 0.14 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 2 ml of N,N-dimethylformamide. 0.12 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure to obtain 0.06 g of [(4-{(dichlorofluoromethyl)thio}-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (43), hereinafter) shown by below formula.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[F:29])[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[F:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[O:16])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3ccncc3F)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(C1CCN(c2ccncc2F)CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl acetate (40 ml) saturated with gaseous HCl was added to a solution of 1-(tert-butoxycarbonyl)-4-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine (2.60 g) in ethyl acetate (20 ml) and the resulting suspension stirred at ambient temperature for 3 hours. Solvent was evaporated to give 1-[1-(3-fluoro-4-pyridyl)piperidin-4-carbonyl]piperazine hydrochloride (2.45 g) as a solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].B1C2CCCC1CCC2.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:21]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C=O)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH2:5][C:20]1[N:21]=[C:22]([NH:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH:23]=[CH:24][CH:25]=1)[CH3:9]
Reactant: COc1ccc(CNc2cccc(Br)n2)cc1
Reactant: C=CCCC(=O)OCC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1cccc(NCc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 4-pentenoate (8.95 g, 69.8 mmol) was treated with 9-BBN (167 mL, 83.7 mmol; 0.5M in THF) at 0° C. then warmed to room temperature and stirred for 16 hours. To this solution was added Pd(OAc)2 (1.57 g, 6.98 mmol), pyridine 16-2 (18.4 g, 62.8 mmol), K2CO3 (14.4 g, 105 mmol), 1,1′-bis(diphenylphosphino)-ferrocene (3.87 g, 6.98 mmol) and DMF (200 mL). The mixture was degassed with argon for 10 minutes then heated to 80° C. for 24 hours. The reaction mixture was cooled and stirred with ethanolamine (20 mL) for 2 hours. The mixture was partitioned between water and EtOAc, extracted with EtOAc (3×), washed with water (3×), then brine, dried (MgSO4) and concentrated. Purification by silica gel chromatography (hexane:EtOAc 3:2) afforded the title compound 16-3 as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:31](=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccc(F)cc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3cc(F)ccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[(4-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.91 (s, 3H), 4.94 (s, 2H), 6.25 (dd, 1H), 6.54 (dd, 2H), 6.75-6.80 (m, 1H), 7.10 (d, 2H), 7.33-7.54 (m, 8H), 7.94 (d, 1H), 7.98 (s, 1H).
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([C:14]1[CH:15]=[C:16]([CH2:20][C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:23](OCCC(C)C)=[O:24]>C(O)C.C(OCC)(=O)C>[C:6]([C:14]1[CH:15]=[C:16]([C:20](=[N:23][OH:24])[C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)CCON=O
Reactant: N#CCc1cccc(C(=O)c2ccccc2)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CC(=NO)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of sodium ethoxide prepared from sodium (1.70 g) and ethanol (40 ml) was added dropwise a solution of 2-(3-benzoylphenyl)acetonitrile (13.6 g) in ethanol (30 ml) at 0° C., and then isoamyl nitrite (12.4 ml) was added dropwise. After stirring at room temperature for 15 hours, the reaction mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and an aqueous saturated solution of sodium chloride. The ethyl acetate layer was dried (MgSO4) and concentrated to obtain 2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile (15.2 g, yield 99%) as crystals. Recrystallization from ethyl acetate-hexane gave an isomer of 2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile as colorless crystals. m.p. 175-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].C(N(CC)CC)C.[C:36](Br)(=[O:38])[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([NH:26][C:36](=[O:38])[CH3:37])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(N)ccc1OC
Reactant: CC(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(NC(C)=O)ccc1OC
Reaction time: 1 h

Procedure:
At 0° C., under an inert atmosphere, 1 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-amino-2-methoxyphenyl)-N-propylamino]thiazole is dissolved in 3.5 ml of dichloromethane. 0.4 ml of triethylamine is added followed by 0.14 ml of acetyl bromide. After 1 hour at room temperature, the reaction mixture is diluted with dichloromethane. The organic phase is washed with water and then dried over sodium sulphate. The evaporation residue is purified on silica gel; eluent cyclohexane/ethyl acetate 1/1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:31])[CH2:16][O:17][CH2:18][CH2:19][O:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:31][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][O:32]2)[CH2:16][O:17][CH2:18][CH2:19][O:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc(OCc3ccccc3)cc2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C

Procedure:
22.7 g of 1-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanol was dissolved in 140 ml of pyridine. The solution was cooled to -20° C. To the solution was added 19 g of p-toluenesulfonyl chloride. The resulting mixture was heated to 0° C. and stirred for 15 hours at the same temperature. The reaction mixture was added to a mixture of 300 ml of ice water and 200 ml of diethyl ether. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 100 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with 1N hydrochloric acid, water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=3/1) to obtain 20.5 g of oily 1-(4-benzyloxyphenyl)-2-[2-(p-toluenesulfonyl)oxyethoxy]ethanol. (3) To a mixture of 20 g of 1-(4-benzyloxyphenyl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol and 40 ml of methylene chloride containing 8.2 g of 3,4-dihydro-2H-pyrane was added 2.3 g of pyridinium p-toluenesulfonate at room temperature. The resulting mixture was refluxed for 30 minutes. The reaction mixture was cooled and added to a mixture of 100 ml of ice water and 100 ml of methylene chloride. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 18.6 g of light yellow oily 1-(4-benzyloxyphenyl)-1-(2-tetrahydropyranyloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane.
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].FC(F)(F)S(O)(=O)=O.[SH:59][C@@H:60]1[CH2:64][N:63]([C:65]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][C:72]([N+:75]([O-:77])=[O:76])=[CH:71][CH:70]=2)=[O:66])[C@H:62]([C:78]([N:80]2[CH2:85][CH2:84][N:83]([CH2:86][CH2:87][O:88][C:89](=[O:91])[NH2:90])[CH2:82][CH2:81]2)=[O:79])[CH2:61]1>C(#N)C>[C:89]([O:88][CH2:87][CH2:86][N:83]1[CH2:82][CH2:81][N:80]([C:78]([C@@H:62]2[CH2:61][C@H:60]([S:59][C:32]3[C@H:33]([CH3:34])[C@@H:29]4[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]4[C:31]=3[C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[CH2:64][N:63]2[C:65]([O:67][CH2:68][C:69]2[CH:70]=[CH:71][C:72]([N+:75]([O-:77])=[O:76])=[CH:73][CH:74]=2)=[O:66])=[O:79])[CH2:85][CH2:84]1)(=[O:91])[NH2:90]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: NC(=O)OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCOC(N)=O)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 28.6 %

Procedure:
91 μl of diphenylphosphoryl chloride and 77 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 152 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 2.0 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 176 μl of diisopropylethyl-amine and a solution of 318 mg of (2S,4S)-4-mercapto-2-[4-(2-carbamoyloxyethyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethane-sulfonate (prepared as described in Preparation 53) in 2.0 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with an aqueous solution of sodium hydrogencarbonate. The mixture was then extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was then removed from the extract by distillation under reduced pressure, and the resulting residue was purified by chromatography through a Lobar column (Merck, LiChroprep Si60, size B), using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent to give 99 mg of the title compound, as a powder.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[C:21](/[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)=[CH:22]/[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)C>>[CH:23]1(/[CH:22]=[C:21](\[C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)/[CH2:20][OH:19])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)/C(=C/C1CCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)CO)cc1
Yield: 100.3 %

Procedure:
Following the method of example 54e, reaction of DIBAL in toluene (268 ml, 1.5 M, 402 mmol) with (E)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-acrylic acid ethyl ester (51.8 g, 160 mmol) affords the title compound as a solid (45 g). MS (m/e): 303.4 (M+Na).
Reaction SMILES: C([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[C:14]=1OC)([CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([O:6]CC)=[O:5])#N.I.S([O-])(O)=O.[Na+]>C(O)(=O)C>[CH2:9]([CH:3]1[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:14]=2[O:5][C:4]1=[O:6])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Yield: 55.4 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]-n-hexanoate (6.5 g), hydriodic acid (58%, 10 ml) and glacial acetic acid (20 ml) was refluxed under heating for 47 hours. After cooling, the reaction mixture was poured into dil. aqueous sodium hydrogen sulfite and extracted with diethyl ether. The extract was washed with water, dil. aqueous sodium hydrogen sulfite and water in turn, dried and evaporated under reduced pressure. To the oily residue was added acetic anhydride (10 ml), and the mixture was refluxed under heating for 10 minutes and evaporated under reduced pressure. Water and ethanol were added to the residue, and the mixture was concentrated under reduced pressure. The oily residue was purified by column chromatography (silica gel 80 g, benzene) to give 3-(n-butyl) 7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (2.8 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH:17]([CH3:31])[CH2:16]1)[CH2:5][CH2:6][O:7]CC1C=CC=CC=1.B(Br)(Br)Br>>[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH:17]([CH3:31])[CH2:16]1)[CH2:5][CH2:6][OH:7]
Reactant: COC(=O)[C@H](CCOCc1ccccc1)N1CC(C)N(c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: BrB(Br)Br
Product: COC(=O)[C@H](CCO)N1CC(C)N(c2ccc(Cl)c(Cl)c2)CCC1=O

Procedure:
In analogy to the procedure described in example 1H, (S)-4-benzyloxy-2-[4-(3,4-dichloro-phenyl)-3-methyl-7-oxo-[1,4]diazepan-1-yl]-butyric acid methyl ester and boron tribromide (after warming up the reaction to maximum to −5° C.) gave after precipitation CH2Cl2/n-pentane 78% of the title compound as a 71:29 mixture of the (R) and (S) diastereomers. Off-white foam, MS: 447.0 (M+OAc−, 2Cl).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][S:48](Cl)(=[O:50])=[O:49])=[CH:43][CH:42]=1>C(Cl)Cl.O>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:48]([CH2:47][C:44]3[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=3)(=[O:49])=[O:50])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccc(Cl)cc3)CC2)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.9 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (6.0 mL) was added (4-chloro-phenyl)-methanesulfonyl chloride (106.7 mg, 0.474 mmol). The reaction mixture was stirred at 0° C. for 10 minutes, then it was warmed to room temperature and stirred at room temperature for four hours. The reaction mixture was diluted with water (25 mL). The resulting mixture was extracted with ethyl acetate (2×25 mL). The organic phase was dried over MgSO4, filtered, and concentrated. Silica gel chromatography (20-25% ethyl acetate in hexanes) provided {4-[1-(4-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (28.5 mg, 24%) as a colorless film. MS cald. For C26H28ClFNO4S [(M+H)+]: 504, obsd. 504.2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]1([N:61]=[C:62]=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:62]([NH:61][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:63])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2ccccc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 51 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and phenyl isocyanate as starting materials in 51% yield. LCMS for C31H32ClN8O2 (M+H)+: m/z=583.2.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][C:3]=1[CH3:13].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:9][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(OCCN)cc(C)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCCNS(C)(=O)=O)cc(C)c1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 2-(4-bromo-3,5-dimethylphenoxy)ethanamine (100 mg) and triethylamine (63 μL) in dichloromethane (2 mL) is added methanesulfonyl chloride (32 μL). The mixture is stirred for 2 hours at 0° C. Then the mixture is partitioned between dichloromethane and water. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 90 mg; LC (method 7): tR=1.01 min; Mass spectrum (ESI+): m/z=322 [M+H]+.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[I:11][C:12]1[C:13]([O:21][CH3:22])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C1COCC1>[I:11][C:12]1[C:13]([O:21][CH3:22])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16]
Reactant: CC(C)(C)O
Reactant: COc1c(I)cccc1C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(I)cccc1C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a cooled (−5° C.) solution of tert-butanol (12.87 mL, 30 mmol) in THF (30 mL) was added, dropwise, BuLi (12.0 mL, 2.5 M in hexanes, 30 mmol). On complete addition, the solution was stirred for 20 minutes. To this solution is added a solution of 3-Iodo-2-methoxy-benzoyl Chloride (8.8 g, 29.8 mmol) in THF (12 mL). On complete addition, the cold bath was removed and stirring continued for 1.5 hours. This solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (50 g silica; eluted with 0-20% ethyl acetate in hexanes) to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C[C:11]1[CH:12]=[C:13]([CH:15]=[C:16](C)[CH:17]=1)N>>[CH3:9][C:8]1[CH:7]=[CH:6][C:4]([NH:5][C:11]2[CH:12]=[CH:13][CH:15]=[CH:16][CH:17]=2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C)cc(N)c1
Reactant: Cc1ccc(N)cc1C
Product: Cc1ccc(Nc2ccccc2)cc1C
Yield: 84 %

Procedure:
The procedure of Example IV is repeated with the exception that 3,4-dimethylaniline was substituted for 3,5-dimethylaniline. After a reaction time of 3.5 hours, the crude reaction product was recrystallized once from hexane to give an 84 percent yield of 3,4-dimethyldiphenylamine having a melting point of 55°-55.5° C.
Reaction SMILES: [Na].[N+](CCC)([O-])=[O:3].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1>C(O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[O:3])=[CH:11][C:12]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: CCC[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 3.5 h

Procedure:
After dissolving sodium metal (0.41 g, 17.8 g-atom) in ethanol (25 ml), nitropropane (1.65 g) and 4-(bromomethyl)-1-fluoro-2-phenoxybenzene (5.00 g) are added and the mixture stirred for 3.5 h. The reaction was filtered and concentrated in vacuo. The residue is taken up in ether and washed with water (10 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (10:90) to afford the title compound as a colorless liquid which is characterized by 1HNMR spectral analyses.
Reaction SMILES: C([NH:4][C:5]([NH2:7])=[NH:6])(=O)C.Br[CH2:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:11]([C:10]1[NH:6][C:5]([NH2:7])=[N:4][CH:9]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)NC(=N)N
Reactant: O=C(CBr)CCc1ccccc1
Solvent: CN(C)C=O
Product: Nc1ncc(CCc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of 1-acetylguanidine (1.34 g, 13.2 mmol) in dimethylformamide (7 ml) a solution of 1-bromo-4-phenyl-butan-2-one (1.5 g, 6.6 mmol) in dimethylformamide (7 ml) was added at 0° C. The mixture was stirred overnight at room temperature and then the solvent was evaporated. Upon addition of ethyl acetate/heptane (1:1) a white solid was formed that was filtered off and washed with ethyl acetate/heptane (1:1). After drying in vacuo the solid was dissolved in a mixture of concentrated hydrochloric acid (2 ml) and methanol (4 ml) and stirred for 2.5 hours at 85° C. The solvent was evaporated and the residue was purified by chromatography (column: Isolute Flash-NH2 from Separtis; eluent: ethyl acetate/methanol=1:1) to yield a light yellow solid (0.063 mg, 5%); MS (EI): 187.2 (M+).