Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].Br[CH2:13][CH2:14][CH2:15]Br.[F-].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH2:15][CH2:14][CH2:13][O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(Br)c(O)c1O
Reactant: BrCCCBr
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c2c1OCCCO2
Temperature: 110 °C
Reaction time: 12 h

Procedure:
3-bromo-6-methoxycatechol (31 g) was dissolved in DMF (50 ml), mixed with 1,3-dibromopropane (36 ml) and potassium fluoride (42 g), stirred for 12 hours while heating at 110° C. The resultant was allowed to stand for cooling, mixed with water, and extracted with ether. The organic layer was washed with an aqueous sodium hydroxide solution, water, and a saturated aqueous sodium chloride solution in that order, dried over manganese sulfate, and evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give Compound IIbr-a (6.7 g, 18%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[Cl:22]>CN(C)C=O.O>[Cl:22][C:13]1[CH:14]=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=[CH:17][C:12]=1[CH2:11][CH:5]([C:4](=[O:9])[CH3:3])[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(C)=O
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in oil, 0.30 g) was added portionwise to a stirred solution of pentane-2,4-dione (0.92 g) in N,N-dimethylformamide (8.0 mL) at 0-10° C. The resulting mixture was stirred at 0-10° C. for 20 minutes and then a solution of 1-bromomethyl-2-chloro-4-methanesulfonylbenzene (2.0 g) in N,N-dimethylformamide (3.0 mL) was added dropwise. The resulting mixture was stirred at room temperature for 5 hours, and then diluted with water and this mixture was extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:4 to 3:7 by volume) gave title compound as a white solid, 1.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS([C:22]1[N:23]([CH3:33])[C:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[N:25][N:26]=1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([O:15][C:22]3[N:23]([CH3:33])[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=4)=[N:25][N:26]=3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Reactant: Cn1c(-c2cccnc2)nnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: CC(Oc1nnc(-c2cccnc2)n1C)c1nnn(-c2cccc(Cl)c2)n1

Procedure:
The title compound is prepared from 1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol (1 mmol), sodium hydride (1.5 mmol), and 3-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH3:13])[CH2:4][CH:5]1[CH2:8][CH:7]([C:9](O)=[O:10])[CH2:6]1)[CH3:2].Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:18][O:17][N:16]([CH3:15])[C:9]([CH:7]1[CH2:8][CH:5]([CH2:4][CH:3]([CH2:12][CH3:13])[CH2:1][CH3:2])[CH2:6]1)=[O:10]
Reactant: CNOC
Reactant: CCC(CC)CC1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCC(CC)CC1CC(C(=O)N(C)OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
3-(2-Ethylbutyl)cyclobutanecarboxylic acid (10.0 g) and chloroform (100 mL) were mixed. To the mixture were added N,O-dimethylhydroxylamine hydrochloride (6.36 g), N,N-diisopropylethylamine (11.3 mL), WSC.HCl (12.5 g) and 4-dimethylaminopyridine (7.96 g) at ice temperature. The mixture was stirred at RT overnight. After an addition of 6 N hydrochloric acid (40 mL) at ice temperature, the aqueous layer was removed. The organic layer was washed with 1 N hydrochloric acid (50 mL), water (50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (13.2 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (355 mg) in DMF (5 mL) was added potassium carbonate powder (548 mg) and 3-trifluoromethylbenzyl bromide (947 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:23](OCCC(C)C)=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:10]=[N:23][NH:5]2
Reactant: CC(C)CCON=O
Reactant: Cc1ccc(N)c(C)c1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: Cc1ccc2[nH]ncc2c1Cl
Reaction time: 18 h
Yield: 58.1 %

Procedure:
the known 3-chloro-2,4-dimethylaniline (14.9 g, 96 mmol) in 250 mL of anhydrous benzene was treated with potassium acetate (9.4 g, 96 mmol) and acetic anhydride (29.4 g, 288 mmol). This mixture was slowly heated to reflux while a precipitate formed. Subsequently, isoamyl nitrite (17 g, 144 mmol) was added rapidly to the refluxing suspension and heating was continued for 18 hours. The cooled suspension was filtered and the solid rinsed with benzene. The combined filtrates were evaporated and the solid residue was dissolved in 200 mL of ethanol containing 1 mL of conc. hydrochloric acid. This mixture was heated under reflux for 5 hours and the solvent was removed in vacuo. The solid residue was washed with 5% sodium bicarbonate and dissolved in ethyl acetate, dried over sodium sulfate and evaporated to give 9.3 g of intermediate solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Li]CCCC.CN([CH:30]=[O:31])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[C:12]([CH:30]=[O:31])=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: COc1cccc(-c2cncn2COCC[Si](C)(C)C)c1
Agent: [Li]CCCC
Product: COc1cccc(-c2cnc(C=O)n2COCC[Si](C)(C)C)c1
Yield: 21.5 %

Procedure:
Reaction of 5-(3-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (470 mg, 1.55 mmol), 2.5 M n-BuLi (800 uL, 2.00 mmol), and DMF (479 uL, 6.18 mmol) for 2 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (111 mg, 22%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.95 (t, 2H, J=9.0 Hz), 3.61 (t, 2H, J=9.0 Hz), 3.89 (s, 3H), 5.8 s (s, 2H), 6.90 (d, 2H, J=9.0 Hz), 7.34–7.42 (m, 3H), 9.89 (s, 1H).
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[CH:7]=[C:8]([CH3:16])[CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:19]1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][C:8]([CH3:16])=[CH:7][C:6]=2[C:4]2[C:3](=[O:17])[NH:30][C:28](=[O:29])[C:27]=2[C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][CH:19]=2)[CH:11]=[CH:12]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cc(C)cc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2c(ccn2C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a mixture of (1,5-dimethyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.51 g, 2.21 mmol) and 2-(1H-indol-3-yl-acetamide (0.35 g, 2 mmol) in DMF (20 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 8.0 mL, 8.0 mmol) at room temperature. The reaction mixture was heated at 50° C. for 18 h, cooled to room temperature, and quenched with hydrochloric acid (1.0 N). After 30 min at room temperature, the mixture was extracted with ethyl acetate and the extract washed with water, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3-(1,5-dimethyl-1H-indol-7-yl)-4-(1H-indol-3-yl]-pyrrole-2,5-dione (400 mg, 56.3%). 1HNMR (DMSO-d6, 400 MHz) 2.28 (s, 3H), 3.64 (s, 3H), 6.39 (d, J=3.07 Hz, 1H), 6.50 (t, J=7.66 Hz, 1H), 6.53 (t, J=7.00 Hz, 1H), 6.74 (d, J=1.4 Hz, 1H), 7.0 (t, J=7.47 Hz, 1H), 7.20 (d, J=3.09 Hz, 1H), 7.35 (d, J=8.11 Hz, 1H), 7.41 (s, 1H), 7.88 (d, J=3.0 Hz, 1H), 11.13 (s, 1H), 11.84 (s, 1H); MS (ES, m/z): C22H17N3O2: 356.2 (M++1); 354.2 (M+−1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-:12].[Na+]>>[N+:8]([C:6]1[CH:7]=[C:2]([OH:12])[C:3]([OH:11])=[CH:4][CH:5]=1)([O-:10])=[O:9]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(O)c(O)c1
Temperature: 60 °C
Yield: 84 %

Procedure:
2-chloro-4-nitro-phenol (64.44 g, 0.4 mole) and 300 ml 4M NaOH solution were refluxed with heating for 6 hours. After cooling down and filtration with vacuuming, the filtrate (crystal) was dissolved in a little warm water (60° C.). The solution was adjusted to pH 2.0 with 10% HCl and cooled down while stirring. After filtration, the filtrate was recrystallized with water to yield 4-nitro-1,2-benzenediol (52.1 g, yield rate 84%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[C:20]([OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][O:28][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
First, 11.1 g of 1-(3-bromopropyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene, 3.31 g of benzoic acid, and 50 ml of N,N-dimethylformamide were placed in a reaction vessel, to which 3.90 g of potassium carbonate was added. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. this crude product was subjected to silica gel chromatography, which afforded 11.6 g (yield, 95%) of 3,5-dichloro-4-(3-benzoyloxypropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene.
Reaction SMILES: O[CH2:2][CH2:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2.P(Br)(Br)(Br)(Br)[Br:15]>C(OCC)C>[Br:15][CH2:2][CH2:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Reactant: BrP(Br)(Br)(Br)Br
Solvent: CCOCC
Product: BrCCC12CC3CC(CC(C3)C1)C2

Procedure:
1-Hydroxy-2-(adamant-1-yl)ethane (901.0 mg, 5.0 mmol) was treated with phosphorus pentabromide(3.0 gm, 7.0 mmol) in diethyl ether and warmed slightly until a noticeable exotherm was observed. The resulting red solution was washed with aqueous sodium bicarbonate solution and dried (Na2SO4). Solvent removal gave crude 1-Bromo-2-(adamant-1-yl)ethane. The material was used as is without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.[S-:19][C:20]#[N:21].[K+].BrBr>C(O)(=O)C>[NH2:21][C:20]1[S:19][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[N:6]=2
Reactant: N#C[S-]
Reactant: COC(=O)c1cccc(Oc2ccc(N)cn2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1cccc(Oc2ccc3nc(N)sc3n2)c1
Yield: 47 %

Procedure:
In the same manner as in Example 98 and using methyl 3-[(5-aminopyridin-2-yl)oxy]benzoate (12.5 g, 51.2 mmol), potassium thiocyanate (34.8 g, 358 mmol), bromine (8.2 mL) and acetic acid (125 mL) as starting materials, the title compound (7.25 g, 47%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]([C:27]1[C:28]([CH3:33])=[N:29][O:30][C:31]=1[CH3:32])=[O:26]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:24][C:25]([C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])=[O:26])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: Cc1noc(C)c1C(=O)CBr
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1noc(C)c1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
A suspension of 150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 154.76 mg (0.709 mmol) of 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 230 mg of (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[S:21]([N:18]1[CH2:19][CH2:20][CH:15]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:14]=2)[CH2:16][CH2:17]1)(=[O:22])=[O:23]
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccccc3Cl)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccccc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.6 %

Procedure:
To a stirred solution of {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (90 mg, 0.19 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (40 mg, 0.95 mmol) in water (1 mL) and the reaction mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (40 mg, 46%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br. s., 1H), 8.03 (d, J=7.8 Hz, 1H), 7.88-7.99 (m, 2H), 7.67-7.79 (m, 3H), 7.61 (t, J=8.8 Hz, 1H), 7.40 (dt, J=8.7, 1.7 Hz, 1H), 7.35 (s, 1H), 3.88 (d, J=12.2 Hz, 2H), 3.72 (s, 2H), 3.46 (t, J=11.7 Hz, 1H), 3.04 (t, J=11.7 Hz, 2H), 1.88-1.96 (m, 2H), 1.64-1.79 (m, 2H); MS cald. for C23H22ClFNO4S [(M−H)−]: 462, obsd. 462.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:2]=1.S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCCCCCc1cccnc1
Solvent: ClCCl
Product: ClCCCCCCCCc1cccnc1

Procedure:
A 3-L flask equipped with a mechanical stirrer, thermometer, and addition funnel was charged with 145.8 g of 3-pyridineoctanol and 1.0 L of methylene chloride. The solution was cooled in an ice bath and 72 mL of thionyl chloride, diluted to 500 mL with methylene chloride, was added dropwise over 15 minutes. The cooling bath was removed and the mixture was heated at a gentle reflux for 1.0 hour. The mixture was again cooled in an ice bath and treated with 750 mL of 3N sodium hydroxide. The separated aqueous phase was extracted with 2×250 mL=500 mL of methylene chloride. The combined organic solutions were dried over sodium sulfate to which was added 10 g of Norite A charcoal. The mixture was filtered through Celite and the solvent was stripped on a rotary evaporator at 45°. The residue was co-stripped with 100 mL of toluene to give 191.3 g (overweight) of the desired 3-(8-chlorooctyl)pyridine as a brown oil which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.[N:10]1([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:14]=[CH:13][CH:12]=[CH:11]1>C(Cl)Cl>[C:1]([C:11]1[N:10]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of acetyl chloride (6.77 ml) in DCM (400 ml) was added tin (IV) chloride (11.14 ml) at -5° C., under nitrogen. 2-(1H-pyrrol-1-yl)-1H-isoindole-1, 3(2H)dione (20.0 g) was then added portion-wise, keeping the temperature below 0° C. The reaction mixture was then stirred at 0° C. for 0.5 hour, at which time it was poured into ice water. The layers were separated and the aqueous phase was extracted with DCM. The combined organics were washed twice with 5% HCl (aq.) and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, DCM) afforded 9.62 g of the product as a solid, m.p. 204°-205° C.
Reaction SMILES: C[O-].[Na+].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.[SH:13][CH2:14][CH2:15][OH:16]>C(O)C>[OH:16][CH2:15][CH2:14][S:13][CH2:11][C:8]1[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccncc1
Reactant: OCCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: OCCSCc1ccncc1
Temperature: 25 °C
Reaction time: 21.5 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (170.1 g., 3.15 moles, 2.1 equiv.) was dissolved in 2.7 1. of absolute ethanol, and the stirred solution cooled in an ice bath. Solid 4-picolyl chloride hydrochloride (97%, 253.6 g., 1.5 moles, 1 equiv.) was added portionwise over approximately 15 minutes. A solution of 2-mercaptoethanol (128.9 g., 1.65 moles), dissolved in 300 ml. of ethanol, was then added dropwise over approximately 30 minutes. The reaction was allowed to warm to room temperature and stirred for 21.5 hours. Diatomaceous earth was added to the reaction mixture, which after brief stirring, was filtered. The filter cake was repulped 2× 1500 ml. of absolute ethanol, the filtrates were combined with the original filtrate, and the combined ethanol solution evaporated to a solid-containing oil (approximately 290 g.). The oil was dissolved in 1500 ml. of hot chloroform, treated with activated carbon, filtered, reconcentrated to oil (274 g.) and chromatographed on 1.5 kg. of silcia gel in a 10 cm. diameter column using chloroform as eluant. Fractions of approximately 3.5 1. were taken. Fractions 3 to 18 were combined, concentrated to oil, the oil taken up in approximately 1 1. of ethyl acetate and evaporated to yield relatively pure 4-(2-hydroxyethylthiomethyl)pyridine [195.7 g., ir (film): 3.17, 3.51, 3.58, 6.27, 9.45 and 12.27μ; pnmr/CDCl3 /TMS/delta: 8.63-8.42 (m, 2H), 7.38-7.18 (m, 2H), 3.73 (t, 2H), 3.72 (s, 2H), 2.98 (s, broad, 1H) and 2.63 (t, 2H) ppm]. On standing, product prepared by this procedure slowly crystallized (m.p. 47°-48° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([CH3:14])[N:5]=[C:4]([NH2:15])[CH:3]=1.[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C(#N)C>[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([NH:21][C:22]([NH:15][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([CH3:14])[N:5]=1)=[O:23])=[O:20]
Reactant: Cc1cc(N)nc(C)c1-c1ccccc1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: CC#N
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2Cl)nc(C)c1-c1ccccc1
Reaction time: 2 h

Procedure:
4,6-Dimethyl-5-phenyl-2-pyridylamine (0.5 gram) was dissolved in 25 ml acetonitrile and reacted with 2-chlorobenzoyl isocyanate (0.6 gram) under nitrogen at room temperature. A precipitate formed immediately and the reaction was stirred for approximately 2 hours. The solid product was collected, washed with a small amount of acetonitrile, and identified by NMR as the desired product, m.p. 176°-189° C.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15][CH3:16])[C@@H:13]([CH3:17])[CH2:12][O:11][C@H:10]1[C:18]([O:20]C)=O)C1C=CC=CC=1.[CH2:22]([NH2:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>>[CH2:22]([NH:29][C:18]([C@H:10]1[C@H:9]([OH:8])[C@@H:14]([O:15][CH3:16])[C@@H:13]([CH3:17])[CH2:12][O:11]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCN
Reactant: COC(=O)[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1OCc1ccccc1
Agent: Cl
Product: CCCCCCCNC(=O)[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1O
Temperature: 90 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
A mixture of methyl (2R,3R,4S,5S)-3-benzyloxy-4-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylate (7 mg, 0.024 mmole) and heptylamine (0.1 ml, 0.68 mmole) was heated at 90° C. for 3 hr. The reaction mixture was adjusted to pH 3 with 0.1N aqueous HCl, and partitioned between ether (10 ml) and water (10 ml). The ether layer was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. A solution of the resulting crude amide in MeOH (5 ml) was stirred under hydrogen atmosphere in the presence of Pd-black (5 mg) at room temperature for 12 hr. The catalyst was removed by filtration and washed with methanol (2 ml×2). The combined filtrate and washings were evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using AcOEt/n-hexane (4:6) as an eluent to give (2R,3R,4S,5S)-N-heptyl-3-hydroxy-4-methoxy-5-methyltetrahydro-2H-pyran- 2-carboxamide (3.4 mg, 50% yield) as an oil; FAB-MS: m/z 288 (MH+). 1H-NMR (CDCl3)d: 0.91 (3H,t,J=6.5 Hz), 1.05 (3H,d,J=7 Hz), 1.25 (10H,br.s), 2.2 (1H,m), 3.10~3.6 (7H,br.m), 3.3 (3H,s), 3.81 (1H,dd,J=2.5 & 12 Hz), 8.0 (1H,br.s).