Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][S-:2].[Na+].[Na+].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[S].Br[CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23]>C(O)C>[F:23][C:22]([F:24])=[CH:21][CH2:20][CH2:19][S:1][S:2][CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23]
Reactant: FC(F)=CCCBr
Reactant: [S-][S-]
Agent: [Na+]
Agent: [S-2]
Agent: [S]
Solvent: CCO
Solvent: O
Product: FC(F)=CCCSSCCC=C(F)F

Procedure:
A solution of sodium disulfide (previously prepared from sodium sulfide nonahydrate (53 g) and sulfur (7.0 g) in ethanol (250 cm3)) was added to 1-bromo4,4-difluorobut-3-ene (50 g) in ethanol (100 cm3). The mixture was gradually heated and stirred under reflux for 2 hours, then cooled and evaporated under reduced pressure. The residue was extracted with diethyl ether, the organic phase filtered to remove sodium bromide and the ether evaporated under reduced pressure to give a liquid which was distilled at 16 mm Hg, bp 120° C. to give the bis-(4,4-difluorobut-3-enyl)disulfide (24 g) as a colourless liquid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([O:15][C:16]2[CH:39]=[CH:38][C:19]([C:20]([C:22]3[CH:23]=[C:24]([CH2:31][CH2:32][CH2:33][C:34]([O:36]C)=[O:35])[N:25]4[C:30]=3[CH:29]=[CH:28][CH:27]=[CH:26]4)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([C:22]3[CH:23]=[C:24]([CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[N:25]4[C:30]=3[CH:29]=[CH:28][CH:27]=[CH:26]4)=[O:21])=[CH:38][CH:39]=2)[CH2:12][CH2:13][CH3:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCC[C@H](Oc1ccc(C(=O)c2cc(CCCC(=O)OC)n3ccccc23)cc1)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC[C@H](Oc1ccc(C(=O)c2cc(CCCC(=O)O)n3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 50.2 %

Procedure:
To a solution of methyl 4-[1-[4-[1-(S)-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyrate (182 mg) in ethanol (4 ml) was added 1N aqueous solution of sodium hydroxide (0.6 ml). The mixture was stirred at 50° C. for 40 minutes, and then poured into a mixture of ethyl acetate and diluted hydrochloric acid. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized with diisopropyl ether to give 4-[l-[4-[l-(S)-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyric acid as white powder (89 mg).
Reaction SMILES: [C-]#N.[Na+].[C:4]1([CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][NH:12][NH2:13].O.[CH3:15][N:16](C)[CH:17]=[O:18]>>[CH3:11][N:12]([C:17]([NH:16][CH2:15][C:5]1[CH:6]=[C:7]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:8]=[CH:9][C:4]=1[CH3:10])=[O:18])[NH2:13]
Reactant: CNN
Reactant: CN(C)C=O
Reactant: Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2ccccc2)cc1CNC(=O)N(C)N
Temperature: 100 °C

Procedure:
1.0 g (4.61 mmol) of 2-methyl-5-phenylbenzyl chloride (produced in the same manner as in Intermediate Production Example 10) is dissolved in 2 ml of anhydrous N,N-dimethylformamide, and to this solution is added 450 mg (6.92 mmol) of sodium cyanide, and the mixture is stirred at 100° C. Subsequently, 2 ml of toluene is added to the reaction solution and the mixture is cooled to 0° C., to this is added 213 mg (4.61 mmol) of methylhydrazine, the mixture is stirred at room temperature, then, to this is added water, and the mixture is extracted with chloroform. The organic layer is washed with saturated saline, end-dried over anhydrous magnesium sulfate, and concentrated to obtain 2-methyl-4-(2-methyl-5-phenylbenzyl) semicarbazide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-:10].[Na+].[CH:12]1[C:17]([CH2:18][Cl-]C([O-])=O)=[CH:16][CH:15]=[C:14]([N+:23]([O-:25])=[O:24])[CH:13]=1.[O:26]1[CH2:31]COCC1>O>[OH:1][C@H:2]1[CH2:6][N:5]([C:31]([O:26][CH2:18][C:17]2[CH:12]=[CH:13][C:14]([N+:23]([O-:25])=[O:24])=[CH:15][CH:16]=2)=[O:10])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: [OH-]
Reactant: C1COCCO1
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
(2S,4R)-(-)-4-Hydroxy-2-pyrrolidinecarboxylic acid [trans-4-hydroxy-L-proline](5.24 g, 40 mmol) in water (40 ml) was treated with 1M aqueous sodium hydroxide (40 ml), cooled in an ice-bath and then treated with 4-nitrobenzylchloroformate (8.64 g, 40 mmol) in 1,4-dioxane (40 ml), added dropwise over 20 min. The mixture was stirred at 0° C. for 3 h. Most of the 1,4-dioxane was removed by evaporation under reduced pressure and ethyl acetate (100 ml) and water (100 ml) were added. The mixture was acidified and the aqueous layer extracted a further two times with ethyl acetate (100 ml). The ethyl acetate layer was dried (MgSO4) and evaporated under reduced pressure to leave an oil which crystallised after trituration under diethyl ether. The crystals were filtered off to give the title compound (8.69 g, 70%) as a mixture of conformers/rotamers, m.p. 136°-137° C. (EtOAc/hexane) (Found: C, 50.30; H, 4.43; N, 8.82 C13H14N2O7 requires C, 50.32; H, 4.55; N, 9.03%); [α]D -38° (c 1 in EtOH); νmax (KBr) 3319, 1737, 1663, 1607, 1518, 1456, and 1342 cm-1 ; δH (250 MHz, (CD3)2CO) 2.20-2.25 (1H, m), 2.25-2.50 (1H, m), 3.50-3.72 (2H, m), 4.4-4.6 (2H, m), 5.18 (d, J 14.2 Hz), 5.29 (s), 5.33 (d, J 14.2 Hz) (together 2H, OCH2Ar, 2 conformers ), 7.66 (2H, m), and 8.23 (2H, m); [Mass spectrum M+ (310)].
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[S:11]([CH3:14])(=[O:13])=[O:12])=O.[C:15]([OH:18])(=O)[CH3:16].[NH:19]1CCC[CH2:21][CH2:20]1.O>ClCCl>[C:20]([C:21]([C:15](=[O:18])[CH3:16])=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[S:11]([CH3:14])(=[O:13])=[O:12])#[N:19]
Reactant: CC(=O)O
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C=O
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)C(C#N)=Cc1ccc(C#N)cc1S(C)(=O)=O

Procedure:
4-Formyl-3-(methylsulfonyl)benzonitrile (3.0 g, 14.34 mmol) and sodium 1-cyanoprop-1-en-2-oxide (1.66 g, 15.8 mmol, 1.1 eq.; cf. R. Troschütz, Archiv der Pharmazie 1984, 317, 709-713) were initially charged in dichloromethane (180 ml). Glacial acetic acid (1.03 ml, 18 mmol, 1.25 eq.) and piperidine (142 μl, 1.43 mmol, 0.1 eq.) were then added, and the mixture was heated under reflux on a water separator (18 h). The reaction solution was then washed once with water (50 ml) and twice with saturated sodium bicarbonate solution (100 ml each), dried over sodium sulfate and concentrated. The solid residue was suspended in six times the amount of ethanol and once more filtered off with suction, and the crystals were washed with ethanol and dried under high vacuum. This gave 2.7 g (70% pure, 48% of theory) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:26]=[N:27][C:28](F)=[CH:29][C:30]=3[CH3:31])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1.O>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[N:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:15][CH:16]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2C(=O)OC[C@H]2C)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of (R)-4-methyloxazolidin-2-one (222 mg) described in Preparation Example 25 in DMF (4 mL) was added sodium hydride (84 mg) at 10° C., and the mixture was stirred for 30 min. Furthermore, [4-(5-bromo-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (447 mg) described in Preparation Example 113 was added, and the mixture was stirred at 80° C. for 3 hr and at 100° C. for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give (R)-3-{5-[4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}-4-methyloxazolidin-2-one (260 mg).
Reaction SMILES: C[C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH3:10].[C:11](#N)[CH:12](CC#N)O.[CH3:18]C[O-].[Na+]>CCO>[CH2:11]([O:9][C:4]1[N:5]=[C:6]([OH:8])[CH:18]=[CH:10][C:3]=1[C:2]#[N:7])[CH3:12]
Reactant: N#CCC(O)C#N
Reactant: CC[O-]
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1C
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(O)ccc1C#N
Yield: 70.7 %

Procedure:
To dimethyl uracil (10.5 g, 75 mmol) in EtOH (75 mL) was added malonitrile (9.9 g, 150 mmol) and EtONa (2.5 M, 60 mL, 150 mmol). The mixture was refluxed for 2 h and the precipitates were collected and washed with EtOH. The solid was treated with 2N aqueous HCl and extracted with EtOAc to provide 2-ethoxy-6-hydroxy-nicotinonitrile (8.7 g, 71%). A portion of this material (8.2 g, 50 mmol) was dissolved in CH2Cl2 (75 mL) followed by addition of PhNTf2 (19.6 g, 55 mmol) and Et3N (6.06 g, 60 mmol). The mixture was allowed to stir at ambient temperature overnight and washed with water and purified by column chromatography to provide trifluoro-methanesulfonic acid 5-cyano-6-ethoxy-pyridin-2-yl ester (15.9 g, coeluted with PhNHTf). A portion of this material (9.5 g, impure) was dissolved in MeOH (40 mL) followed by addition of PdCl2CH2Cl2dppf (1.4 g, 1.7 mmol) and Et3N (6.5 g, 65 mmol). The mixture was heated at 50° C. under CO (100 psi) for 6 h. The mixture was purified by column chromatography to provide 5-cyano-6-ethoxy-pyridine-2-carboxylic acid methyl ester (2 g, 32% over 2 steps). A portion of this material (1.5 g, 7.3 mmol) was dissolved in EtOH/H2O (5:3, 15 mL) followed by addition of LiOH (640 mg, 15 mmol). The mixture was stirred for 30 min and 2N aqueous HCl was added to adjust the acidity to pH of 1. Precipitates were collected and washed to provide 5-cyano-6-ethoxy-pyridine-2-carboxylic acid (1.0 g, 71%).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][C:35]1[CH:50]=[CH:49][C:38]([C:39]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)=[O:40])=[CH:37][C:36]=1[O:51][CH3:52].CC(C)CC(O)C>CO>[CH2:16]([C:8]1([CH2:18][CH3:19])[C:7](=[O:20])[N:6]([CH3:21])[C:5]2[C:11](=[N:12][C:2]([NH:34][C:35]3[CH:50]=[CH:49][C:38]([C:39]([NH:41][CH:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)=[O:40])=[CH:37][C:36]=3[O:51][CH3:52])=[N:3][CH:4]=2)[N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9]1)[CH3:17]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CCC1(CC)CN(C(C)C)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Solvent: CO
Product: CCC1(CC)CN(C(C)C)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O
Temperature: 120 °C

Procedure:
10-chloro-4,4-diethyl-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 198; 100 mg, 0.322 mmol), p-toluene sulphonic acid monohydrate (153 mg, 0.81 mmol) and 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 84 mg, 0.322 mmol) were added to 4-methyl-2-pentanol (7 mL). The reaction was heated at 120° C. over the weekend. The reaction mixture was loaded on to an SCX column (10 g), pre-wet with methanol, washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound, after drying under vacuum at 70° C., as a white solid (97 mg, 56%)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(O[C@H]2CC[C@H](N)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of trans-4-aminocyclohexanol (3 g, 26 mmol) in DMF (130 mL) at 0° C. was added 60% sodium hydride in oil. The reaction mixture was stirred at 0° C. for 1 h and then 4-fluorobenzonitrile (3.9 g, 32.6 mmol) was added. It was heated to 60° C. for 2 h and stirred for 12 h at room temperature. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried, filtered, and concentrated under reduced pressure to provide the titled compound (2.5 g, 44% yield). 1H NMR (300 MHz, DMSO-d6): δ7.72 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 4.48-4.34 (m, 1H), 2.68-2.55 (m, 1H), 2.07-1.94 (m, 2H), 1.85-1.71 (m, 2H), 1.46-1.11 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.N12CCCN=C1CCCCC2.[CH2:23]([OH:26])[C:24]#[CH:25]>O1CCCC1.C(OCC)C.[Cu]I.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>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:25]#[C:24][CH2:23][OH:26])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCO
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: OCC#Cc1cccc(C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
To a degassed solution of 1-bromo-3-trifluoromethylbenzene (20.0 g, 88.8 mmol) in tetrahydrofuran (160 ml) were in the following order added: copper(I) iodide (506 mg, 2.66 mmol), tetrakis(triphenylphosphine)palladium (3.06 g, 26.6 mmol), and 1,8-diazabicyclo-[5.4.0]undec-7-ene (16.22 g, 106.6 mmol). The resulting mixture was degassed one more time, cooled in an ice bath and a solution of propargyl alcohol (5.94 g, 106.6 mmol) in tetrahydrofuran (10 mL) was added over period of 20 min. The reaction mixture was slowly heated up to 55° C. and then stirred at this temperature for 16 h. The mixture was diluted with diethyl ether (400 mL), washed with water (100 mL), 5% hydrochloric acid (100 mL) and saturated aqueous solution of sodium hydrogen carbonate (80 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 85:15) affording 3-(3-trifluoromethylphenyl)prop-2-yn-1-ol.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)[CH:18]=1
Reactant: COc1ccccc1CN
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3ccccc3OC)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-methoxybenzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 450.5. HPLC (Condition A), Rt: 4.72 min (HPLC purity: 92.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH:12]1[C:27]([OH:29])=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:13][CH:12]1[C:27]([O:29][CH3:32])=[O:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a flask containing N,N'-dibenzyloxycarbonylpiperazine-2-carboxylic acid (Step 1, 12.83 g, 32.20 mmol) dissolved in dry DMF (50 mL) is added methyl iodide (5.6 mL, 90.00 mmol) and potassium carbonate (4.60 g, 32.20 mmol). The mixture is stirred for 4 hours at ambient temperature under an inert atmosphere. The reaction is concentrated in vacuo, diluted with ethyl acetate (150 mL), washed with water (3×50 mL) and saline, dried over MgSO4, concentrated in vacuo, and chromatographed on silica gel (70-230 mesh), eluting with hexane/ethyl acetate (50/50). The appropriate fractions are combined (Rf =0.55, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, NMR (CDCl) 7.31, 5.15, 5.12, 4.70, 4.1-2.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9](OC(=O)CC)(=O)[CH2:10][CH3:11].[CH2:18]([N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([C@H:28]([C:43]2[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=2)[C:46](Cl)=[O:47])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][Si](C(C)(C)C)(C)C)[CH:30]=2)[C@@H:23]([CH3:52])[CH2:22]1)[CH:19]=[CH2:20]>>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][CH2:9][CH2:10][CH3:11].[CH2:18]([N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([C@H:28]([C:43]2[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=2)[C:46]([N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)[CH2:9][CH2:10][CH3:11])=[O:47])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[C@@H:23]([CH3:52])[CH2:22]1)[CH:19]=[CH2:20]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: Nc1cccc(F)c1
Reactant: CCC(=O)OC(=O)CC
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CCC)c3cccc(F)c3)c2)C[C@H]1C
Product: CCCNc1cccc(F)c1

Procedure:
3-Fluoro-N-propylaniline [NMR (DMSO-d6, 200 MHz): δ 0.96 (t, J=7.3 Hz, 3H); 1.56 (m, 2H); 2.97 (q, 6.9 Hz, 2H); 5.93 (br m, 1H); 6.22-6.43 (m, 3H); 7.06 (q, J=7.8 Hz, 1H)] was prepared from 3-fluoroaniline and propionic anhydride, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-propylbenzamide as a light beige solid. NMR (DMSO-d6, 200 MHz): α0.9-1.05 (m, 9H); 1.5 (m, 2H); 1.7 (m, 1H); 2.05 (m, 1H); 2.3 (m, 1H); 2.5 (m, 2H); 2.7 (m, 1H); 2.85 (m, 1H); 3.8 (m, 2H); 4.8 (s, 1H); 5.1 (d, J=10 Hz, 1H); 5.2 (d, J=16 Hz, 1H); 5.8 (m, 1H); 6.45 (d, J=8 Hz, 1H); 6.6 (s, 1H); 6.7 (d, J=8 Hz, 1H); 6.9 (d, J=8 Hz, 1H); 7.0-7.4 (m, 9H); 9.3 (s, 1H). [α]D20 =+4.3° (abs ethanol, c=1.5). Calc. for C32H38FN3 O2HCl 0.75 H2O: C, 67.95; H, 7.22; N, 7.43; Cl, 6.27. Found: C, 67.72; H, 7.19; N, 7.49; Cl, 6.30. Mass spectrum (CI--CH4) m/e: 516 (M+1, 100%), 515 (M, 22%), 362 (30%), 153 (73%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([C@H:37]1[O:39][CH2:38]1)Cl>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:35][CH:37]2[CH2:38][O:39]2)=[CH:9][CH:10]=1
Reactant: ClC[C@@H]1CO1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CO2)cc1

Procedure:
Analogously to Example 148e, 5.60 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 2.05 ml of (S)-(+)-epichlorohydrin are reacted. The title compound is obtained as a colourless oil. Rf=0.24 (1:2 EtOAc-heptane); Rt=5.66.
Reaction SMILES: [C:1]1([OH:15])[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:16]Br.O>C(O)(=O)C>[Br:16][C:4]1[C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13][C:14]=2[C:1]([OH:15])=[CH:2][CH:3]=1
Reactant: Oc1cccc2c1Sc1ccccc1S2
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(Br)c2c1Sc1ccccc1S2

Procedure:
Thianthren-1-ol (6.5 g, 27.98 mmol) was dissolved in glacial acetic acid (100 ml) and to this solution was added bromine (17.1 μl, 13.99 mmol) in a dropwise fashion over 30 minutes. Water (200 ml) was added to the amber solution and the mixture extracted with EtOAc (3×100 ml). The combined organic extracts were then washed with saturated potassium bicarbonate solution (3×100 ml), dried using MgSO4, filtered and concentrated in vacuo to give the title compound. (7.56 g, 87%). m/z (LC-MS, ESP):, RT=4.92 min, (M++1)=309.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:19][C@H:18]2[CH2:20][CH2:21][O:22][C:23]2[C:28]([F:29])=[CH:27][C:26]([CH2:30][C:31](O)=[O:32])=[C:25]([F:34])[CH:24]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][NH:36][CH3:37].C1COCC1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH3:35][N:36]([CH3:37])[C:31](=[O:32])[CH2:30][C:26]1[C:25]([F:34])=[CH:24][C:23]([O:22][CH2:21][CH2:20][C@@H:18]2[CH2:19][C@@H:17]2[CH:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH2:13]2)=[C:28]([F:29])[CH:27]=1
Reactant: CNC
Reactant: O=C(O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[2-((1S,2R)-2-{1-[(benzyloxy)carbonyl]piperidin-4-yl}cyclopropyl)ethoxy]-2,5-difluorophenyl}acetic acid (313 mg, 0.661 mmol) in 2.5 ml anhydrous DMF at RT was added dimethylamine, 2.0 M solution in THF (0.661 ml, 1.32 mmol) and N,N-diisopropylethylamine (0.562 ml, 3.31 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (503 mg, 1.32 mmol) was added into the solution and stirred at RT overnight. The reaction mixture in 12 ml water was extracted with 12 ml ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on Biotage column (25 g silica gel) using a gradient eluent of 0-50% ethyl acetate in hexanes (800 ml) to afford the title compound. LC/MS (m/z): 501.4 (M+H)+.