Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:10]([CH2:11]Cl)=[CH:9][CH:8]=[CH:7][N:6]=1>CCO.O>[Cl:4][C:5]1[C:10]([CH2:11][C:1]#[N:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: [C-]#N
Reactant: ClCc1cccnc1Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1cccnc1Cl
Temperature: 25 °C

Procedure:
In a 3 L reactor, set for reflux under positive nitrogen pressure and using a bleach scrubber, was prepared a solution of potassium cyanide (68.32 g, 1.04M) in EtOH (136 mL) and water (255 mL). The mixture was heated to reflux, at which point a solution of 2-chloro-3-(chloromethyl)pyridine (Intermediate 1; 170.0 g, 1.04M) in EtOH (170 mL) was added dropwise over 30 minutes. The whole mixture was maintained at reflux for a further 150 minutes. The mixture was then allowed to cool just below boiling point and the equipment set for distillation. A total of 8.5 volumes of EtOH were removed. On cooling, half a volume of water was added. At a temperature of 40° C., the solution was seeded and crystallised instantaneously. The thick beige slurry was allowed to cool to ambient temperature and then to 0° C. This mixture was filtered, rinsed with cold water (2 vols) and dried at 45° C. in a vacuum oven overnight. The title compound was afforded as a beige solid in excellent yield and purity (126.9 g, 80%). δH (d6-DMSO, 300 MHz) 8.45 (1H, dd), 8.00 (1H, dd), 7.50 (1H, dd), 4.15 (2H, s). LCMS (ES)+ RT 2.15 min, m/e 153.01 & 155.01 (M+1 & M+3, Product).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CO>[CH2:15]([N:9]1[C:8]2[C:7](=[O:13])[NH:6][C:5](=[O:14])[N:4]([CH3:3])[C:12]=2[N:11]=[CH:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A 10% aqueous sodium hydroxide solution (10 ml) was added to a suspension of 3-methylxanthine (4.15 g) in methanol (25 ml) and the mixture was stirred for 1 hour at 70° C. Benzyl bromide (4.275 g, 2.97 ml) was added dropwise at 70° C. and the mixture was stirred at 70-80° C. for an additional 5 hours. After cooling to room temperature, the mixture was treated with water (50 ml). The precipitate was filtered, dissolved in 1 N aqueous sodium hydroxide solution (50 ml) and the solution was acidified to pH 4-5 with concentrated hydrochloric acid. The precipitate was filtered and washed with water (3×20 ml) to provide 7-benzyl-3-methylxanthine (4.45 g).
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH2:15][O:16][C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:34])[CH2:25][C:26]([CH2:32][CH3:33])([CH2:30][CH3:31])[C:27]([OH:29])=[O:28])[CH:20]=[CH:21][CH:22]=3)=[N:12]2)=[CH:7][CH:6]=1>C(OCC)C.O1CCCC1>[CH3:3][O:28][C:27](=[O:29])[C:26]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:25][C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][C:11]2[CH:10]=[CH:9][C:8]3[C:13](=[CH:14][C:5]([F:4])=[CH:6][CH:7]=3)[N:12]=2)[CH:18]=1)=[O:34]
Reactant: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)OC

Procedure:
A solution of diazomethane in diethyl ether is added at 0° to a solution of 1.9 g of 4-[3-(7-fluoro-2-quinolinylmethoxy)phenylamino]-2,2-diethyl-4-oxobutanoic acid (Example 3) in 150 ml of tetrahydrofuran until a yellow colour remains established. The yellow solution is immediately concentrated by evaporation to give the title compound in the form of a colourless oil which crystallises on being left to stand in a refrigerator, m.p. 92°-93°; IR (methylene chloride): 1735 cm-1 (C=O).
Reaction SMILES: [ClH:1].CNC.CCN(C(C)C)C(C)C.C(OC([NH:21][C@@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:23]([OH:25])=O)=O)(C)(C)C.CN(C(O[N:41]1[N:49]=[N:48][C:43]2C=CC=C[C:42]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[ClH:1].[NH2:21][C@@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:23]([N:49]([NH:41][CH3:42])[NH:48][CH3:43])=[O:25]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNN(NC)C(=O)[C@@H](N)Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of dimethylamine hydrochloride (153 g, 187 mmol) in DMF (8 mL) was added DIPEA (2 mL, 6.55 mmol), (S)-2-tert-butoxycarbonylamino-3-pyridin-2-ylpropionic acid (0.50 g, 1.87 mmol, Acros) and TBTU (0.60 g, 1.87 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was dissolved in methanol (15 mL). To this was added 4M hydrochloric acid in dioxane (20 mL) and the reaction stiffed at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (100 mL) and ethyl acetate (2×100 mL). The aqueous layer was evaporated to dryness to give a solid, which was recrystallised from ethanol to give the title compound as a pale brown solid. mr/z (ES+)=194.
Reaction SMILES: [C:1]([C:9]1[CH:40]=[CH:39][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:38]=[CH:37][C:23]([CH2:24][CH:25]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41][O:42][NH2:43]>>[CH2:30]([CH:25]([CH2:24][C:23]1[CH:37]=[CH:38][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:39]=[CH:40][C:9]([C:1](=[N:43][O:42][CH3:41])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:21][CH:22]=1)[C:26]([O:28][CH3:29])=[O:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CON
Reactant: COC(=O)C(Cc1ccccc1)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(Cc2ccccc2)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8](OC)[CH:7]=1.Cl[C:16]1[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(CC(C)(C)C)(C)C>[CH:2]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)=[CH:10][CH:11]=1)=[O:3]
Reactant: N#Cc1cnc(Cl)cn1
Reactant: COc1cc(C2OCCO2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC(C)CC(C)(C)C
Product: N#Cc1cnc(Oc2ccc(C=O)cc2)cn1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 81.8 %

Procedure:
Dissolve 4-[1,3]dioxolan-2-yl-2-phenol (Example 388, Part C2) (1.70 g, 10.2 mmol), 5-chloropyrazine-2-carbonitrile (Example 404, Part A) (1.50 g, 10.7 mmol) and K2CO3 (3.71 g, 26.9 mmol) in DMA (27.0 mL) and isooctane (13.4 mL). Beat at 110° C. for about 2.25 hours. Cool to room temperature and quench with water (100 mL). Extract with dichloromethane (3×100 mL). Wash the extract with saturated aqueous NaHCO3 (1×50 mL) and brine (1×75 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 0-30% ethyl acetate in hexanes. Concentrate the eluant, then take the solid up in 88% formic acid (46 mL) and stir at room temperature for 4 hours. Dilute the reaction mixture with water (50 mL). Extract with dichloromethane (2×100 mL). Wash the extract with saturated aqueous NaHCO3 (1×50 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 30% ethyl acetate in hexanes to give the title compound (1.88 g, 77.7%): TOF MS ES+ 225.1 (M)+, HRMS calcd for C12H7N3O2 225.0538 (M)+, found 225.0527, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=11.5 min, 100% purity.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2[nH]ccc2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 5-amino-indole (Aldrich) according to the method described in Example 1c. Melting Point: 80-82° C. (ethyl acetate)
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19]C(C2CCNCC2)=N[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:31]=[C:32]=[N:33]CCCN(C)C.C1C=CC2N(O)N=NC=2C=1.ONC(N)=N>CN(C=O)C.O>[NH2:33][C:32]1[N:22]=[C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:19][N:31]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)o2)N1OCc1ccccc1
Agent: N=C(N)NO
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Nc1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
A solution of (2S,5R)-6-(benzyloxy)-2-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (2.0 g, 7.25 mmol), EDCI (1.53 g, 7.98 mmol) and HOBT (1.08 g, 7.98 mmol) in DMF (15 mL) was stirred at rt for 0.5 h. 1-Hydroxyguanidine (0.653 g, 7.98 mmol) was then added and the reaction mixture was stirred for an additional 0.5 h. The resulting solution was treated under microwave at 100° C. for 1.5 hrs. The mixture was poured into water and extracted with EtOAc (2×). The combined organic layers were then washed with water (20 mL), and saturated sodium chloride (20 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (2:1 EtOAc/petroleum ether) to give (2S,5R)-2-(3-amino-1,2,4-oxadiazol-5-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (1.0 g, 44%). (ESI-MS (EI+, m/z): 316 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.[Cu][C:22]#[N:23].C(OCC)(=O)C>CS(C)=O>[F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:22]#[N:23])=[N:6]1
Reactant: Cc1ncc2c(I)nn(Cc3cccc(F)c3F)c2n1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ncc2c(C#N)nn(Cc3cccc(F)c3F)c2n1
Temperature: 150 °C

Procedure:
1.360 g (3.35 mmol) of 1-(2,3-difluorobenzyl)-3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 330 mg (3.68 mmol) of copper(I) cyanide were initially charged in 10 ml of absolute DMSO and the mixture was heated at 150° C. for 2 h. After cooling, the mixture was added to 200 ml of ethyl acetate and washed with a mixture of concentrated aqueous ammonia solution and semisaturated aqueous ammonium chloride solution (v/v=1:3). The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. 1.040 g (purity 92%, 100% of theory) of the target compound were obtained.
Reaction SMILES: Br[CH:2]([CH2:18]C)[C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:17])[NH:10]2)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[O:23]1[CH2:24][CH2:25][N:20]([CH:2]([CH3:18])[C:3]([C:5]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]3[C:6]=2[CH2:7][CH2:8][C:9](=[O:17])[NH:10]3)=[O:4])[CH2:21][CH2:22]1
Reactant: CCC(Br)C(=O)c1ccc(OC)c2c1CCC(=O)N2
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C(=O)c1ccc(O)c2c1CCC(=O)N2)N1CCOCC1

Procedure:
5 g of 5-(α-bromopropionyl)-8-hydroxy-3,4-dihydrocarbostyril (IV) was suspended in 30 ml of benzene, and 4.2 ml of morpholine (III) was added to the suspension followed by allowing the mixture to react for 4 hours while heating under refluxing. The reaction mixture was filtered and the filtrate was washed with water followed by concentration under reduced pressure to remove any remaining water. The resulting residue was dissolved in 50 ml of isopropanol, and the solution was adjusted to a pH of 2 - 3 with concentrated hydrochloric acid. The viscous precipitate formed upon ice-cooling was separated and dissolved in acetone by heating. After allowing the solution to cool, the precipitate formed was dissolved in 30 ml of water and adjusted to a pH of 7.5 - 8 with sodium bicarbonate. The precipitate formed upon ice-cooling was filtered and dissolved in 10 ml of a 47% aqueous hydrobromic acid followed by concentration under reduced pressure. The residue thus obtained was washed with 10 ml of ethanol and recrystallized from ethanol to obtain 2.6 g of white amorphous 5-(α-morpholinopropionyl)-8-hydroxy-3,4-dihydrocarbostyril (IIb) hydrobromide monohydrate having a melting point of 235° - 236° C (with decomposition).
Reaction SMILES: CON(C)[C:4](=[O:22])[C:5]([CH3:21])([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][N:14]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:24]([Mg]Br)=[CH2:25].Cl>O1CCCC1>[CH3:21][C:5]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][N:14]=1)([CH2:6][CH:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)[C:4](=[O:22])[CH:24]=[CH2:25]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C(C)(CC1CCOCC1)c1ccc(SC)cn1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(C)(CC1CCOCC1)c1ccc(SC)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A solution of N-methoxy-N,2-dimethyl-2-[5-(methylsulfanyl)pyridin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (401 mg) in tetrahydrofuran (4.8 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 4.76 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 3 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (250 mg, yield 69%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.O>O1CCCC1>[Br:12][C:9]1[NH:8][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(-c2ccc[nH]2)s1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2ccc(Br)[nH]2)s1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-Methyl-2-(1H-pyrrol-2-yl)-1,3-thiazole (100 mg, 0.61 mmol) synthesized in Example (3c) was dissolved in tetrahydrofuran (7 mL), and cooled to 0° C. N-Bromosuccinimide (108 mg, 0.61 mmol) was added, and stirring was carried out at room temperature for 18 hours under nitrogen atmosphere. Water (10 mL) was added, and the solution was separated with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used as it is in the next reaction.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH3:12][C:13]([OH:19])([C:15]([CH3:18])(O)[CH3:16])[CH3:14]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][C:13]1([CH3:14])[C:15]([CH3:18])([CH3:16])[O:11][B:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]3[O:19][C:13]([CH3:14])([CH3:12])[C:15]([CH3:18])([CH3:16])[O:2]3)[CH:4]=2)[O:10]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OB(c2cccc(C3OC(C)(C)C(C)(C)O3)c2)OC1(C)C
Yield: 76.8 %

Procedure:
(3-formylphenyl)boronic acid (5 g, 33.3 mmol), 2,3-dimethylbutane-2,3-diol (19.70 g, 167 mmol) and p-toluensulfonic acid monohydrate (0.317 g, 1.667 mmol) were dissolved in toluene (278 mL) and refluxed with a Dean-Stark equipment for 3 h until reaction completion. The mixture was dried under reduced pressure and the residue diluted with AcOEt (250 mL) and washed three times with abundant water, once with saturated NaClaqueous (250 mL), anhydrified over Na2SO4 and the solvent removed under reduced pressure. The crude was purified via flash chromatography on silica gel using a Biotage 100G+50G SNAP with a gradient of hexane and AcOEt to give the title compound (8.5 g, 77%) as white solid.
Reaction SMILES: CN(C)[C:3](=O)[S:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]=O.[OH-].[Na+].ClC[C:21]#[N:22]>O.CO>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[CH:13]=[C:3]([C:21]#[N:22])[S:4][C:5]=2[CH:10]=1
Reactant: COc1ccc(C=O)c(SC(=O)N(C)C)c1
Reactant: N#CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C#N)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
(Ref: Gallagher, T; Pardoe, D. A.; Porter, R.; Tetrahedron Lett.; 2000, 41(28), 5415–5418.) To a solution of S-(2-formyl-5-methoxyphenyl) dimethylthiocarbamate (1.08 g, 4.5 mmol) in water (4 mL) and methanol (8 mL) was added sodium hydroxide (199 mg, 4.9 mmol), this was heated to reflux for 16 hours. The reaction was cooled to room temperature and chloroacetonitrile (0.28 mL, 4.5 mmol) was added in one portion and the mixture the stirred at room temperature for 1 hour. The methanol was removed in vacuo, and water (10 mL) added. The aqueous layer was extracted with diethyl ether (3×20 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography with a gradient of 0–30% ethyl acetate in iso-hexane to give the title compound as a colourless solid (390 mg, 46%); δH (300 MHz, CDCl3) 7.80–7.70 (1H, m, ArH), 7.29 (2H, m, ArH), 7.11–7.01 (1H, m, ArH) and 3.85 (3H, s, OCH3). M+23=212.0. νmax/cm−1 [film] 2213.50 (m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1>[CH3:19][O:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of N-t-butoxycarbonyl isonipecotic acid (8.8 g, 34.9 mmol), in a 10% mixture of methanol in benzene (250 ml), was added a 2.0 M solution of trimethylsilyldiazomethane in hexanes, dropwise, until a consistent yellow color was obtained (~30 ml). After vigorous gas evolution had ceased, cooling was removed and the reaction mixture stirred for 1 h at room temperature. The mixture was then treated dropwise with glacial acetic acid until all yellow color had dissipated. It was then stirred 15 min. and concentrated in vacuo to a pale yellow oil. This material was purified by column chromatography on silica with 20% EtOAc/hexane as eluent. The appropriate fractions were combined and concentrated in vacuo to afford the product as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH2:35][CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].CS(O[CH2:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[CH3:47][O:46][CH2:45][CH2:44][CH2:43][CH2:42][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH2:35][CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:14]1)=[O:11]
Reactant: COCCCCOS(C)(=O)=O
Reactant: CCCN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCN(C(=O)c1nc2ccccc2n1CCCCOC)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 15 h
Yield: 94.8 %

Procedure:
tert-Butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(propyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (1.97 g) and 4-methoxybutyl methanesulfonate (754 mg) were dissolved in DMA (50 ml), cesium carbonate (1.93 g) was added and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (0:10-5:5) was concentrated under reduced pressure to give the object product (2.19 g).
Reaction SMILES: B(Br)(Br)Br.C([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])C1C=CC=CC=1.O>C(Cl)Cl>[F:27][C:21]([F:26])([C:22]([F:23])([F:24])[F:25])[CH2:20][CH2:19][CH2:18][S:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:12]
Reactant: FC(F)(F)C(F)(F)CCCSCCCCOCc1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: OCCCCSCCCC(F)(F)C(F)(F)F
Temperature: -78 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
BBr3 (1M in DCM, 2.9 mL, 2.9 mmol) was added dropwise to a solution of (4-(benzyloxy)butyl)(4,4,5,5,5-pentafluoropentyl)sulfane (340 mg, 0.95 mmol) in DCM (5 mL) cooled to −78° C. The temperature was allowed to warm up to room temperature and the mixture was stirred for 18 h. Water was slowly added and the reaction mixture was stirred for 10 min. The two layers were separated and the aqueous layer was extracted with DCM (3×). The organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 50 to 100% EtOAc/hexanes to afford 171 mg of 4-((4,4,5,5,5-pentafluoropentyl)thio)butan-1-ol as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]4[CH2:33][C:32](=[O:34])[C:29]5([CH2:31][CH2:30]5)[CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:35])[NH:6]2.[H-].[Na+].S(OC)([C:41]1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]4[CH2:33][CH:32]([O:34][CH3:41])[C:29]5([CH2:31][CH2:30]5)[CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:35])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCCN1CC(=O)C2(CC2)C1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCCN1CC(OC)C2(CC2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The above product from Example 2 (60 mg) was dissolved into DMF (4 ml) and cooled at 0° C. NaH (1.1 eq) was added to the reaction and stirred for 10 minutes. To the reaction was added TsOMe (1.2 eq), the solution was heated at 80° C. for two hours. The reaction was quenched with water and extracted with EtOAc followed by washing with water, then brine and dried over Na2SO4. The solution was evaporated and purified by silica column to give the titled product. Mass: (M+1), 492