Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8](C(Cl)=O)[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si](C=[N+]=[N-])(C)C.[BrH:27].[C:28]([OH:31])(=O)[CH3:29]>C(#N)C>[C:1]([C:5]1[CH:9]=[C:8]([C:28](=[O:31])[CH2:29][Br:27])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1cc(C(=O)Cl)n(Cc2ccccc2)n1
Reactant: Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Product: CC(C)(C)c1cc(C(=O)CBr)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1 g (3.6 mmol) of 3-(tert-butyl)-1-benzylpyrazole-5-carbonyl chloride (Maybridge, Cornwall, UK) was dissolved in dry acetonitrile (4 mL) and 4.5 mL (9 mmol) of 2 M trimethylsilyldiazomethane in hexanes (Aldrich, Milwaukee, Wis., USA) was added. After stirring 1 h 20 min at room temperature, the mixture was cooled on an ice bath for 5 min. To this, 30% hydrogen bromide in acetic acid (2 mL, 10 mmol) was added dropwise over 15 min. This was stirred an additional 15 minutes on an ice bath. Filtration of the precipitated solid and evaporation of the solvents gave 1-[3-(tert-butyl)-1-benzylpyrazol-5-yl]-2-bromoethan-1-one (1.47 g, quantitive yield) as an orange solid. 1H-NMR (DMSO-d6; 300 MHz) δ7.33-7.06 (m, 5H), 7.08 (s, 1H), 5.64 (s, 2H), 4.57 (s, 2H), 1.28 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C16H19N2OBr, 335.1 and 337.1 (M+H), found 335.6 and 337.6.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24].O1CCOCC1>C1COCC1>[ClH:24].[CH2:1]([NH:8][C:9]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(NCc1ccccc1)C1CCNCC1
Reaction time: 1 h

Procedure:
tert-butyl 4-(benzylcarbamoyl)piperidine-1-carboxylate (95 mg, 0.298 mmol) was dissolved in anhydrous THF (3 mL), and 4M HCl/dioxane (1 mL, 4.0 mmol) was added at rt. The solution was allowed to stir for 1 h, at which time the resulting precipitate was collected over a filter. Residual mineral acid was removed in vacuo, and the material was used directly in the next reaction without further characterization. (Yield: 76 mg, 0.298 mmol, 100%)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][CH:7]1[CH2:12][CH:11]2[CH2:13][CH:8]1[C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=12.[C:20](Cl)(=[O:22])[CH3:21].O>C(Cl)Cl>[C:20]([CH:12]1[CH:11]2[CH2:13][CH:8]([C:9]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=32)[CH:7]1[O:6][CH3:5])(=[O:22])[CH3:21]
Reactant: COc1cccc2c1C1CC2CC1OC
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1C1CC2C(C(C)=O)C1OC

Procedure:
23.5 g of aluminum chloride are added in small portions to a mixture of 30 g of 1,4-dimethoxybenzonorbornene and 13.8 g of acetyl chloride in 300 cm3 of methylene chloride. At this stage, a check is made that all the starting material has been converted. The reaction mixture is poured into 300 cm3 of water. The organic phase is washed with sodium bicarbonate, then with water, and dried over magnesium sulphate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:20])=[C:18](Br)[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([CH:21]3[CH2:23][CH2:22]3)[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: Fc1ccc2c(c1Br)OCCN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc2c(c1C1CC1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A mixture of 4-benzyl-9-bromo-8-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine (500 mg, 1.49 mmol), cyclopropylboronic acid (153 mg, 1.78 mmol), potassium carbonate (617 mg, 4.46 mmol), dioxane (3 ml) and water (3 ml) was deaerated with argon gas, and bis(triphenylphosphine)palladium(2) dichloride (52.2 mg, 0.0744 mmol) was added. The mixture was stirred under an argon atmosphere for 3 hr at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (408 mg, 92.1%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][OH:11].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:19][S:20]([O:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:22])=[O:21]
Reactant: OCC(CC1CCCCC1)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(CC1CCCCC1)c1ccc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
To a stirred and cooled (ice-bath) mixture of 22 parts of 2,4-dichloro-β-(cyclohexylmethyl)benzeneethanol and 50 parts of pyridine are added dropwise 8.8 parts of methanesulfonyl chloride. Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted twice with trichloromethane. The combined extracts are washed twice with a diluted hydrochloric acid solution and once with water, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 16.5 parts of 3-cyclohexyl-2-(2,4-dichlorophenyl)propyl methanesulfonate; mp. 105.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([NH:22][CH3:23])([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][N:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:23]
Reactant: Fc1cc(Br)c(CCl)cc1F
Reactant: CNC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(Cc1cc(F)c(F)cc1Br)C(C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of 1-bromo-2-chloromethyl-4,5-difluorobenzene are dissolved in 5 ml of acetonitrile. 540 mg of caesium carbonate and 206 μl of tert-butylmethylamine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness, after which the product is isolated as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=O)=[CH:5][CH:4]=1.[C:13](#[N:17])[CH2:14][C:15]#[N:16]>C(O)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[C:14]([C:13]#[N:17])[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: N#CCC#N
Reactant: COc1ccc(C=CC=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=CC=C(C#N)C#N)cc1
Yield: 90.7 %

Procedure:
To 0.52 g (3.2 mmol) of the aldehyde from step (a) and 0.26 g (4 mmol) malononitrile in 30 ml ethanol was added 2 drops piperidine and the reaction mixture was refluxed for 40 minutes, cooled, filtered and washed with ethanol to yield 0.61 g (90% yield) of an orange solid, m.p. 160° C.
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([OH:32])[C@H:27]1[OH:33].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[I:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][C@@H:28]([OH:32])[C@H:27]5[OH:33])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCC[C@@H](O)[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1[C@H](O)CCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Temperature: 120 °C
Yield: 30.5 %

Procedure:
To a suspension of 6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (350 mg, 0.8 mmol) and (1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride (258 mg, 1.6 mmol), prepared as described in Gauthier Errasti, et al, Org. Lett. 2009, 13, 2912-2915, in anhydrous DMA (1.5 mL) was added DIEA (402 μL, 2.4 mmol). The mixture was heated in a sealed tube at 120° C. for 15 h. The mixture was cooled to rt and partitioned between EtOAc (150 mL) and 0.5 M aq K2CO3 (100 mL). The organic layer was separated and washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford (1R,2S,3R)-3-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (127 mg, 32%) as a yellow solid. LCMS (ESI) m/z 521 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:54]=[O:55].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 70 °C
Reaction time: 21 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 3j (2.4 g, 3.23 mmol) was dissolved in 20 mL 1,4-dioxane, followed by addition of 5 mL 37% formaldehyde solution and 13 mL 1 M sodium hydroxide. The reaction mixture was stirred for 21 hours at 70° C. Thereafter, the reaction mixture was extracted with ethyl acetate (50 mL×3) after 20 mL of saturated sodium chloride solution were added. The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 3k (1.6 g, yellow grease), yield: 64.0%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([NH:33][C:34]1[CH:43]=[C:42]2[C:37]([C:38]([CH3:45])=[CH:39][C:40](=[O:44])[O:41]2)=[CH:36][CH:35]=1)=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>C1(C)C=CC=CC=1>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([NH:33][C:34]1[CH:43]=[C:42]2[C:37]([C:38]([CH3:45])=[CH:39][C:40](=[O:44])[O:41]2)=[CH:36][CH:35]=1)=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[F:53][C:54]([C:55]([OH:57])=[O:56])([F:59])[F:58]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)ccc12
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@@H](N)Cc3ccccc3)ccc12

Procedure:
Boc-Phe-Gly-Leu-Gln-AMC (0.63 g) was deblocked by treatment with trifluoroacetic acid at about 23°. Toluene was added to the resulting reaction mixture, and then the combined solvents were evaporated at reduced pressure , leaving a residue. This residue was redissolved in toluene, and the solvent was then evaporated again to leave a residue, which was dried in vacuo overnight over solid potassium hydroxide to provide 0.69 g of white, solid H-Phe-Gly-Leu-Gln-AMC trifluoroacetate. TLC with 1-butanol:acetic acid: water (4:1:1) showed two spots, Rf 0.58 and Rf 0.51.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]([CH2:21][NH2:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][S:24]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)(=[O:26])=[O:25]>>[NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:10]([CH2:21][NH:22][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:29][CH:30]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CN(c2cccc(N)c2)CCN1Cc1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Product: CS(=O)(=O)Nc1ccc(C(=O)NCC2CN(c3cccc(N)c3)CCN2Cc2ccccc2)cc1

Procedure:
In a manner similar to Preparation 3, react 4-(3-aminophenyl)-1-(phenylmethyl)-2-piperazinemethanamine (4.8 g, 16 mmol) with 4-[(methylsulfonyl)amino]benzoyl chloride (3.8 g, 16 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[NH:11][CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Yield: 76.3 %

Procedure:
A mixture of (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (14.58 g, 63 mmol), benzaldehyde (7.39 g, 70 mmol), sodium triacetoxyborohydride (16.0 g, 76 mmol) and 1,2-dichloroethane (100 mL) was stirred at 20° C. then quenched with saturated aqueous sodium hydrogen carbonate (500 mL). The mixture was extracted with DCM (3×100 mL) and the combined organic extracts dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-25% EtOAc in 40-60 petroleum ether) gave the title compound (15.4 g, 76%) as an oil. MS: [M+H]+=321. 1H NMR (CDCl3): 7.42-7.12 (5H, m), 4.12-3.88 (2H, m), 3.85-3.55 (4H, m), 3.27 (1H, dd), 2.91-2.79 (1H, m), 2.73 (1H, dd), 2.63 (1H, s), 2.33 (1H, dd), 1.49 (9H, s), 1.21 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CC(C)=O>[CH2:35]([O:34][C:32]([N:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][C:17](=[O:18])[N:12]([C:5]2[CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=2[F:24])[C:13]1=[O:23])=[O:33])[CH3:36]
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)n1c(C(F)(F)F)cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with potassium carbonate and ethyl chloroformate in acetone there is obtained 1-ethoxycarbonyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 1H-NMR (CDCl3, 400 MHz): 7.30 ppm (d,1H), 6.83 ppm (d,1H), 6.37 ppm (s,1H), 4.51 ppm (q,2H), 4.45 ppm (m,1H), 1.42 ppm (t,3H), 1.37 ppm (d,6H);
Reaction SMILES: [C:1]([O:22]CC)(=[O:21])/[CH:2]=[CH:3]\[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[Na+].O.Cl>CO>[C:1]([OH:22])(=[O:21])/[CH:2]=[CH:3]\[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCC=CC=CC=CC=C/C=C\C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCC=CC=CC=CC=C/C=C\C(=O)O
Reaction time: 1.5 h
Yield: 96 %

Procedure:
To a solution of ethyl cis-eicosapentaenoate (5 g, 15.15 mmol) in methanol (100 mL) was added an aqueous solution of sodium hydroxide (6 g, 150 mmol, in 20 mL of water) at rt and stirred for 1.5 h. The reaction mixture was poured into ice cooled water and acidified with dil. HCl. The solution was extracted with dichloromethane (3×50 mL) and the combined layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the acid (4.4 g, 96%) as an oil; LCMS (ESI, negative ion mode): m/z 301 (M-H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29](I)=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[O:35]1[CH2:40][CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1>>[O:35]1[CH2:36][CH:37]=[C:38]([C:29]2[CH:30]=[C:31]([CH3:32])[C:26]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[C:10]4[C:6]=3[CH2:7][CH2:8][C@H:9]4[O:11][C:12]3[CH:25]=[CH:24][C:15]4[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=4[CH:13]=3)=[C:27]([CH3:34])[CH:28]=2)[CH2:39][CH2:40]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(I)cc5C)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C6=CCOCC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4-iodo-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane following a procedure analogous to that described in Step 4 of Intermediate 2. LC (method 8): tR=0.92 min; Mass spectrum (ESI+): m/z=551 [M+Na]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH:8]=[O:9].[BH4-].[Na+]>CO>[CH3:1][S:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][OH:9]
Reactant: CSc1ccsc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CSc1ccsc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
3.36 g of 3-methylthio-2-thiophenecarboxaldehyde and 802 mg of sodium borohydride were suspended in 20 ml of methanol, and the mixture was stirred at room temperature for one hour. The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then the layer was dried on anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:5), to give 3.16 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.C(N(CC)CC)C.Br[CH2:37][C:38]([NH2:40])=[O:39]>C(#N)C>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][N:19]1[CH2:37][C:38](=[O:39])[NH2:40])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: NC(=O)CBr
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CC(N)=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (200 mg, 0.48 mmol, 1 equiv), in anhydrous acetonitrile (3 mL), at room temperature, under nitrogen atmosphere, was added triethylamine (0.2 mL, 1.44 mmol, 3 equiv) followed by bromoacetamide (80 mg, 0.58 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 18 h, and evaporated to dryness. The residue obtained was first purified over silica gel, with an eluant of 7% methanolic-ammonia/dichloromethane. The desired fractions were collected, evaporated to dryness, and repurified by HPLC (to remove, the side-product from the reaction of the base with bromoacetamide). After lyophilization the desired title compound for example 40 was obtained (2.0 mg) as a white fluffy powder: HPLC: Rt=4.11 min (220.0 nm); 1H NMR (300 MHz, CD3OD) δ (rotamers) 5.46 (d, J=5.5, 1), 4.47 (dd, J=3.02, 2.7, 1.1), 4.31–4.25 (m, 3.3), 4.11(d, J=3.02, 1.6), 2.31(s, 3), 1.65–1.52 (m, 9.5), 1.12–1.09 (m, 10.3). MS (ESPOS): 476.5 [M+H]+, (ESNEG): 474.5[M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.[C:14]([Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34]I)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]1=2)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Reactant: CC(C)(C)[Si](OCC(F)CI)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CC(F)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.9 %

Procedure:
6-Methoxypyrido[2,3-b]pyrazin-3(4H)-one (215 mg, 1.213 mmol) and tert-butyl(2-fluoro-3-iodopropoxy)diphenylsilane (805 mg, 1.820 mmol) were dissolved in N,N-dimethylformamide (6 ml). Cesium carbonate (553 mg, 1.698 mmol) was added to the solution and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 399 mg (67%) of the title compound in the form of a light orange solid.
Reaction SMILES: [CH2:1]([C:7]12[S:14][CH2:13][C:10]([CH2:15][CH2:16][CH3:17])([CH2:11][S:12]1)[CH2:9][O:8]2)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C([O-])(=[O:20])C.[Na+].ClC1C=CC=C(C(OO)=O)C=1.O>C(#N)C>[CH2:1]([C:7]12[S:12][CH2:11][C:10]([CH2:15][CH2:16][CH3:17])([CH2:13][S:14]1=[O:20])[CH2:9][O:8]2)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: CC(=O)[O-]
Reactant: C#CCCCCC12OCC(CCC)(CS1)CS2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C#CCCCCC12OCC(CCC)(CS1)CS2=O

Procedure:
A mixture of 1-(hex-5-ynyl)-4-n-propyl-2-oxa-6,7-dithiabicyclo-[2.2.2]octane (0.75 g., 1 equivalent), anhydrous sodium acetate (2.0 g.) and 3-chloroperbenzoic acid (85%, 1.12 g. 2.5 equivalents) was stirred at 20° in dry acetonitrile (50 ml.) for 18 hours. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with sodium hydrogen carbonate solution, water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. After purification by chromatography on silica (eluting with ethyl acetate), 1-(hex-5-ynyl)-4-n-propyl-2-oxa-6,7-dithiabicyclo[2.2.2]octane-6-oxide was obtained as a colourless solid (0.35 g.).