Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.C1(N(C2N=C(C)ON=2)C)CC1.[CH:32]1([CH2:35][C@H:36]([NH2:43])[C:37]2[N:41]=[C:40]([CH3:42])[O:39][N:38]=2)[CH2:34]C1>>[CH:35]1([CH:36]([NH:43][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:37]2[N:41]=[C:40]([CH3:42])[O:39][N:38]=2)[CH2:32][CH2:34]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Agent: Cc1nc(N(C)C2CC2)no1
Product: Cc1nc(C(NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can e.g. be prepared in a similar manner than (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e)) as starting materials, MS (EI): m/e=420.0 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]=[CH2:8].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].C1C[O:24]CC1>>[C:16]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]=[CH2:8])(=[O:24])[CH:17]=[CH2:18]
Reactant: C1CCOC1
Reactant: C=CC(=O)Cl
Reactant: C=COCCCCO
Solvent: CCN(CC)CC
Product: C=COCCCCOC(=O)C=C

Procedure:
A 125 milliliter single-neck flask was charged with 11.6 grams (100 millimole) 4-hydroxybutylvinyl ether, 15.4 grams (150 millimoles) triethylamine, and twenty milliliters tetrahydrofuran. This solution was stirred magnetically and cooled in an ice bath. A solution of 9.05 grams (105 millimoles) acryloyl chloride dissolved in 20 milliliters THF was then dripped in over the course of forty-five minutes. The mix was stirred another hour while the temperature was allowed to rise to room temperature. The THF and excess triethylamine were removed on the rotary evaporator. The residue was extracted with three 20 ml portions of toluene and the toluene phase was rinsed with 20 ml deionized water. The toluene phase was dried with ten grams anhydrous magnesium sulfate and the toluene was removed to yield a mobile yellow liquid. The product weighed 12.3 grams (72% of theory). This liquid had major IR absorptions at 1723, 1635, 1616, 1408, 1188, 959, 809, and 731 wavenumbers.
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:22]1([C:28]2[O:32][C:31]([C:33]3[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=3)=[N:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[C:22]1([C:28]2[O:32][C:31]([C:33]3[CH:38]=[CH:37][C:36]([C:2]4[C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:9]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=5)=[C:8]5[C:3]=4[CH:4]=[CH:5][CH:6]=[CH:7]5)=[CH:35][CH:34]=3)=[N:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Brc1c2ccccc2c(-c2cccnc2)c2ccccc12
Reactant: OB(O)c1ccc(-c2nnc(-c3ccccc3)o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2nnc(-c3ccc(-c4c5ccccc5c(-c5cccnc5)c5ccccc45)cc3)o2)cc1
Temperature: 120 °C
Yield: 68.3 %

Procedure:
In a 100 mL three-necked flask were placed 0.66 g (2.0 mmol) of 3-(10-bromo-9-anthryl)pyridine, 0.63 g (2.4 mmol) of 4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenylboronic acid, 0.45 g (4.0 mmol) of sodium carbonate, 25 mL of toluene, 3 mL of water, and 6 mL of ethanol. The mixture was degassed by being stirred under reduced pressure, and the atmosphere in the flask was replaced with nitrogen. To this mixture was added 58 mg (0.050 mmol) of tetrakis(triphenylphosphine)palladium(0), and the resulting mixture was refluxed under a nitrogen stream at 120° C. for 23 hours. After a predetermined time has passed, water was added to this mixture, and the aqueous layer was extracted with ethyl acetate. The obtained extract and the organic layer were combined and washed with saturated brine, and then the organic layer was dried with magnesium sulfate. The obtained mixture was subjected to gravity filtration, and the resulting filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography (a 5:1 ratio of toluene to ethyl acetate). Recrystallization from a mixed solvent of toluene and hexane gave 0.65 g of a solid in 69% yield, which was the desired substance.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5]([CH3:13])=[CH:4][C:3]1=[O:14].[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>COC(O)C>[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:12][C:9]2[CH:10]=[C:11]3[C:6]([C:5]([CH3:13])=[CH:4][C:3](=[O:14])[N:2]3[CH3:1])=[CH:7][CH:8]=2)[CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NC1CCN(CCCCl)CC1)c1ccccc1
Reactant: Cc1cc(=O)n(C)c2cc(O)ccc12
Agent: COC(C)O
Product: Cc1cc(=O)n(C)c2cc(OCCCN3CCC(NC(=O)c4ccccc4)CC3)ccc12
Yield: 67 %

Procedure:
In a manner analogous to that described in Example 10, by the reaction of 1,4-dimethyl-7-hydroxy-2-oxo-1,2-dihydroquinoline with 3-(4-benzamidopiperidino)-propyl chloride in methoxyethanol, there is obtained, in a yield of 67% of theory, 7-[3-(4-benzamido-piperidino)-propoxy]-1,4-dimethyl-2-oxo-1,2-dihydroquinoline; m.p. 193°-195° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](O)=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].[C:13]([O-:16])([O-])=O.[K+].[K+].[Cl:19][CH2:20]/[CH:21]=[CH:22]\CCl>C(#N)C>[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:13][O:16][C:5]1[C:6]([O:11][CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: ClC/C=C\CCl
Reactant: COc1cc(C(C)=O)ccc1O
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C(C)=O)c1OC/C=C\CCl
Yield: 106.8 %

Procedure:
A stirred mixture of 4hydroxy-3-methoxyacetophenone (16.6 g, 10 mmole), K2CO3 (14 g, 100 mmol) and cis-1,4-dichloro-2-butene (Aldrich, 15 g, 120 mmol) in acetonitrile (250 ml) was heated at reflux for 2.5 hours. The mixture was filtered and concentrated to an oil. Purification was by flash chromatography. The fractions containing the purest product were combined and concentrated to give white crystals, 7.7 g, 30%. This was recrystallized from ether to give analytical pure (Z)1-[[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone (2.72 g), m.p.=6466.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]([C:11]([OH:13])=[O:12])[NH:2]1.[OH-].[Na+].C(Cl)Cl.O.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(Cl)Cl.C(Cl)(Cl)Cl.Cl>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:2]2[C@@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)(=[O:31])=[O:30])=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(O)[C@H]1Cc2ccccc2CN1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 37 %

Procedure:
(3R)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid (5.32 g) and sodium hydroxide (2.40 g) are added to a mixture of methylene chloride-water (200 ml-200 ml), and thereto is added dropwise a solution of 4-nitrophenylsulfonyl chloride (6.62 g) in methylene chloride (100 ml) under ice cooling over a period of 30 minutes. The mixture is stirred under ice cooling for 3 hours, and thereto are further added sodium hydroxide (1.20 g) and a solution of 4-nitrophenylsulfonyl chloride (3.32 g) in methylene chloride (60 ml) in this order. The mixture is stirred under ice cooling for 2 hours, and further stirred at room temperature for 17 hours, and the reaction mixture is diluted with chloroform and 10% hydrochloric acid. The chloroform layer is collected and washed with water and then with an aqueous saturated saline solution, dried over sodium sulfate and then treated with active carbon. Undissolved materials are filtered off from the chloroform layer, and the solvent is distilled off under reduced pressure. The residue is purified with a silica gel column chromatography (eluent, chloroform) and recrystallized from ethyl acetate-hexane to give (3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (4.01 g) as colorless crystals.
Reaction SMILES: C[O-].[Na+].C1CCC([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])CC1.[C:19]([O:25][CH3:26])(=[O:24])[C:20]([O:22]C)=O.Cl.[CH:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.CCOCC>[CH:28]1([C:16]2[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH2:10][C:20](=[O:22])[C:19]([O:25][CH3:26])=[O:24])=[CH:14][CH:15]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(=O)C(=O)OC
Reactant: c1ccccc1
Reactant: O=C(CC1CCCCC1)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To 22 ml of dry benzene there was added, under nitrogen atmosphere, 1.68 g (31.2 mMol) of sodium methoxide. There was then slowly added with stirring a solution of 6.06 g (30 mMol) of the 4-cyclohexyl acetophenone prepared in Step A above and 3.54 g (30 mMol) of freshly recrystallized dimethyl oxalate in 40 ml of benzene. The reaction mixture was cooled and soon after addition a yellow crystalline precipitate formed. The reaction mixture was allowed to warm to room temperature and stirred for an additional hour. There was then added 75 ml of ether and 24 ml of 2 N hydrochloric acid with 6 ml of water. The mixture was shaken for about 15 minutes, until all of the solid dissolved. The organic layer was then separated, washed with a small amount of water, and dried over magnesium sulfate. The solvent was then evaporated, the residue partially crystallized on cooling, and then crystallized from 3:1 petroleum ether:benzene. After cooling, 3.33 g of yellow solid product, m.p. 96°-98° C., was filtered off.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.N1C=CC=CC=1.P(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a room temperature slurry of 2.5 g of product from Example 19, 10 ml of acetonitrile and 0.339 g of pyridine is added dropwise, over 3 minutes, 2.11 g of phosphorus tribromide. The reaction is stirred at room temperature for 1 hour, diluted with methylene chloride and concentrated in vacuo. The residue is dissolved in methylene chloride, filtered through a silica gel pad and concentrated in vacuo to give 2.65 g of the desired product as pale yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:34]=[CH:33][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16](=[O:32])[C@@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18][C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1)=O.[CH:35]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:35]1([NH:40][CH2:1][C:3]2[CH:34]=[CH:33][C:6]3[N:7]=[C:8]([N:10]4[CH2:11][CH2:12][N:13]([C:16](=[O:32])[C@@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18][C:19]5[S:20][CH:21]=[CH:22][CH:23]=5)[CH2:14][CH2:15]4)[S:9][C:5]=3[CH:4]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(C=O)cc3s2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(CNC4CCCC4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 1-(4-(6-formylbenzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (45 mg), cyclopentylamine (12 mg), and sodium triacetoxyborohydride (29 mg) were combined in DCM (1 mL), and the resulting mixture stirred at room temperature overnight, then heated to reflux for 24 hours. The resulting mixture was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate, extracted with DCM, and chromatographed (0 to 5% MeOH in DCM) to yield (S)-tert-butyl 1-(4-(6-((cyclopentylamino)methyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6]([CH2:8]P(=O)(OCC)OCC)[N:7]=1)[CH3:2].[H-].[Na+].[CH3:19][O:20][CH2:21][O:22][C:23]1[C:27]([CH:28]=O)=[CH:26][N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1.O>O1CCCC1>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:28]/[C:27]2[C:23]([O:22][CH2:21][O:20][CH3:19])=[N:24][N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:7]=1)[CH3:2]
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1csc(CC)n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCOC)cs1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of diethyl [(2-ethyl-1,3-thiazol-4-yl)methyl]phosphonate (4.64 g) in tetrahydrofuran (75 mL) was added sodium hydride (60% in oil, 0.96 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (6.32 g) was added to the reaction mixture, and the mixture was heated under reflux for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:1, v/v) to give 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a pale-yellow oil (4.49 g, yield 66%).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C:7]1[C:8]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])=[N:9][CH:10]=[CH:11][CH:12]=1.C(O)C(F)(F)F.[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1>C(N(CC)CC)C>[Cl:25][C:26]1[N:27]=[C:28]([NH:5][CH2:6][C:7]2[C:8]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])=[N:9][CH:10]=[CH:11][CH:12]=2)[C:29]([C:33]([F:36])([F:34])[F:35])=[CH:30][N:31]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Solvent: OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of B5 and trifluoroethanol (120 mL) was treated with triethylamine (TEA) (16.6 mL) and stirred at 25° C. for 1 hour. In a separate reaction flask, a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (13.2 g, 60.8 mmol) and trifluoroethanol (120 mL) was cooled to −45° C. The cold 2,4-dichloro-5-trifluoromethylpyrimidine solution was then treated drop-wise with the solution containing B5 and stirred at −45° C. for 2 hours. The mixture was allowed to warm to 25° C., and it was stirred at 25° C. for about 20 hours. The reaction mixture was then concentrated and cooled to 0° C. The resultant white mixture was diluted with EtOAc (15 ml), and the solids collected by filtration. The white solids were then washed with water and EtOAc to provide C9. Yield: 0.7 g, 45%. 1H NMR (400 MHz, d6-DMSO) δ: 3.07 (s, 3H), 3.29 (s, 3H), 4.68 (d, 2H), 7.39 (m, 1H), 7.72 (d, 1H), 8.40 (s, 1H), 8.50 (t, 1H); ESI-MS: 396.0 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.Cl.[Br:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CN([CH:24]=[O:25])C>C1COCC1>[Br:14][C:15]1[C:20]([CH:24]=[O:25])=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: Brc1ccncc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cnccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a stirred solution of diisopropylamine (9.02 mL, 63.3 mmol) in THF (75 mL) at −78° C. was added n-butyllithium (1.6 M in hexane) (30 mL, 76 mmol) dropwise under nitrogen atmosphere. After complete addition the solution was stirred for 30 min at −78° C. 4-Bromopyridine HCl (5 g, 31.6 mmol) was added portionwise and the resultant solution stirred at −78° C. for 1 h. DMF (2.94 mL, 38.0 mmol) was then added dropwise at −78° C. to the solution. The reaction mixture was warmed to room temperature slowly and stirred for 12 h. The reaction mixture was quenched with 3 N HCl and stirred for 2 h. The solution was neutralized with saturated sodium bicarbonate solution, extracted with EtOAc (75 mL), dried over sodium sulfate and concentrated under reduced pressure to give 4-bromonicotinaldehyde (3.75 g, 20.16 mmol, 64% yield). The crude product was used without purification in the next step. 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.00 (s, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.62 (d, J=5.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)c1nc(-c2ccccc2)c2snc(-c3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and phenylboronic acid: MS (m/z) 395.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][S:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][NH2:5].C(N(CC)CC)C.[Cl:36][CH2:37][CH2:38][CH2:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl.O1CCCC1>[Cl:36][CH2:37][CH2:38][CH2:39][S:40]([NH:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][S:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CN)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCCCl)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 93 mg (0.223 mM) of 2-methoxy-3-octadecylcarbamoylthiopropylamine IVa6 and 40.4 μl (3.9 mM) of triethylamine in 5 ml of dichloromethane and 2 ml of tetrahydrofuran is added 29.8 μl (3.3 mM) of 3-chloropropanesulfonyl chloride with ice-cooling, and the mixture is stirred for 2 hours and at room temperature for an additional 30 minutes. The product is isolated by dichloromethane extraction and the dichloromethane layer is washed with an aqueous sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by the column chromatography on silica gel with a benzene-ethyl acetate (4:1) mixture as an eluent to give 83 mg (0.149 mM) of 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIIa6 as a colorless powder in 67% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)CC(CCCCO)CCCc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CC(CCCCOS(C)(=O)=O)CCCc1cccnc1
Reaction time: 1 h

Procedure:
To a solution of 1.28 g (4 mmol) of methyl 8-hydroxy-2,2-dimethyl-4-[3-(3-pyridyl)propyl]octanoate in 20 mL methylene chloride at 0° C. is added 0.9 mL (6.5 mmol) triethylamine followed by 0.4 mL (5.2 mmol) methanesulfonyl chloride. After 1 hour, the reaction is diluted with methylene chloride and washed with saturated sodium bicarbonate, water and brine. The organic phase is dried, filtered and evaporated to give methyl 8-methanesulfonyloxy-2,2-dimethyl-4-[3-(3-pyridyl)propyl]-octanoate as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[O:16]([CH:8]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][N:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc(OC(Oc2ccccc2)c2ccccn2)cc1

Procedure:
To a solution of 10.42 grams (g) (0.032 mole (m)) of 6-chloro-2-(diphenoxymethyl)pyridine, 8.02 g (0.079 m) of triethylamine in 200 milliliters (ml) of absolute ethanol in a Parr shaker bottle was added 0.5 g of 5 percent palladium on charcoal. Hydrogen was passed over the liquid surface using a Parr hydrogenator until ~3 pounds (0.3 m) had been consumed. The reaction mixture was filtered and the solvent removed by evaporation under reduced pressure. The residue was poured into a solution of 50 ml of water and 50 ml of 10 percent sodium hydroxide. This solution was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and the solvent stripped away under vacuum. The residue was heated at 0.02 millimeters of mercury to 110° C. to remove lower boiling impurities. The above named product was recovered as a pale yellow oil in a yield of 6.8 g and was ~99 percent pure. The Nuclear Magnetic Resonance spectrum (NMR) confirmed the product. The product has a refractive index of nd25 =1.5946 and upon analysis was found to have carbon, hydrogen and nitrogen contents of 77.78, 5.56 and 4.92 percent, respectively, as compared with the theoretical contents of 77.98, 5.24 and 5.05 percent, respectively, as calculated for the above named compound (Compound 1).