Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:29][C:28]=1[CH:38]=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[Cl:26][C:27]1[N:31]=[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:29]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])(=[O:11])=[O:10])=[CH:5][CH:4]=2)[C:28]=1[CH:38]=[O:39]
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1S(=O)(=O)c1ccc(CBr)cc1
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C=NS(=O)(=O)c1ccccc1S(=O)(=O)c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Yield: 12.8 %

Procedure:
1.6 g of 2-(4-bromomethylbenzenesulfonyl)-N-dimethylaminomethylenebenzenesulfonamide, 680 mg of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde and 1.4 g of K2CO3 are stirred at RT for 3 days in 15 ml of anhydrous DMF. The reaction mixture is then diluted with 200 ml of EA and washed three times with 50 ml of a saturated aqueous Na2CO3 solution each time. It is dried over MgSO4 and the solvent is removed in vacuo. Chromatography on silica gel using MTB yields 240 mg of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=S(=O)(c1ccc(Oc2cncc(Br)c2)cc1)N1CCCC1
Temperature: 120 °C
Yield: 59.1 %

Procedure:
A mixture of 5-bromo-3-pyridinol (2.61 g, 15 mmol), dimethylacetamide (50 mL), 1-((4-fluorophenyl)sulfonyl)pyrrolidine (5.8 g, 25 mmol) and potassium carbonate (4.1 g, 30 mmol) was heated at 120° C. for 18 h, then cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (200 mL) and the organic phase washed with water (3×100 mL) and brine (100 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography, eluting with ethyl acetate/cyclohexane (20/80, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 3.4 g (59%) of a red solid (m.p. 148° C.)
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[NH:5][C:6]=1[Br:7].[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[N:5]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:6]=1[Br:7]
Reactant: Brc1nc(C2CC2)[nH]c1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1Br
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A solution of 4,5-dibromo-2-cyclopropyl-1H-imidazole (60 g, 226 mmol) in THF (150 mL) was added dropwise over 50 minutes under nitrogen to a stirring mixture of sodium hydride (95%, 6.3 g, 250 mmol) in dry THF (150 mL) at 0° C. The reaction mixture was stirred 30 minutes and 2-(trimethylsilyl)ethoxymethylchloride (SEMCl, 40 mL, 38 g, 226 mmol) was added dropwise over 50 minutes at 0° C. After stirring for 1 hour, the reaction was slowly quenched with water (20 mL) and added EtOAc (500 mL). The mixture was washed with water (2×750 mL) and the combined aqueous portions were back extracted with EtOAc (200 mL). The combined organic portions were washed with brine (1 L), dried (Na2SO4), and concentrated. The resulting residue was dissolved in heptane (200 mL) and the resulting solution was passed through a pad of silica gel, eluting with heptane (4×500 mL) and EtOAc-heptane (1:4, 2×250 mL) to give 4,5-dibromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (79 g, 199 mmol, 88%) as a pale yellow solid after concentration: LCMS(m/z) 394.9 (MH+), tR=1.20 minutes, 1H NMR (400 MHz, CDCl3) δ ppm-0.04-0.05 (m, 9H), 0.87-1.12 (m, 6H), 1.88-2.04 (m, 1H), 3.55-3.66 (m, 2H), 5.37 (s, 2H).
Reaction SMILES: [CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:20](S)CCCCC>>[CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:20]
Reactant: CCCCCSc1c[nH]nc1C1CN2CCC1CC2
Reactant: CCCCCCS
Product: CCCCCCSc1c[nH]nc1C1CN2CCC1CC2
Yield: 25 %

Procedure:
Compound 49F was prepared following the procedure as described for the synthesis of compound 49B (see Scheme 10) using hexane-1-thiol as reagent. Subsequent purification by flash chromatography (EtOH) afforded compound 49F.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]([CH3:19])=[CH:13][CH2:14]CC([O-])=O)=[CH:8][CH:7]=1)([O-:5])=[O:4].C(=O)([O-])[O-:23].[K+].[K+]>O>[N+:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]([CH3:19])=[CH:13][CH2:14][OH:23])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: CC(=CCCC(=O)[O-])COc1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=CCO)COc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 176.5 %

Procedure:
Into methanol (1,200 ml) and water (400 ml) were dissolved 120 g (0.25 mol) of [4-(p-nitrophenoxy)-3-methyl-2-butenyl]acetate. With stirring at room temperatures, 40 g (0.29 mol) of potassium carbonate were added therein, and stirred for one hour. The reaction liquid was added into water and extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off, whereby 98.5 g of the title compound were obtained. (Yield: 98.5%)
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Na].[CH2:12](Br)[CH:13]([CH3:15])[CH3:14]>C(O)C>[CH2:12]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH2:10])=[O:9])[CH:13]([CH3:15])[CH3:14]
Reactant: NC(=O)c1ccccc1O
Reactant: CC(C)CBr
Agent: [Na]
Solvent: CCO
Product: CC(C)COc1ccccc1C(N)=O

Procedure:
Salicylamide (68.5 g.; prepared as described by R. Bogoczek, Farm. Polska, 1960, 16, 26) was added to a solution of sodium (11.5 g.) in anhydrous ethanol (400 ml.). Isobutyl bromide (60 ml.) was then added, and the mixture was stirred and heated to reflux overnight. The ethanol was evaporated, and sufficient water was added to the residue to dissolve the sodium bromide. The oil which did not dissolve was extracted with chloroform, the extract was washed twice with 2N sodium hydroxide solution and once with water, dried over magnesium sulphate, filtered and evaporated. The residue was triturated with light petroleum (b.p. 40°-60° C.) to give 2-isobutoxybenzamide, which was pure enough for use in the next stage of the synthesis. A pure sample, m.p. 125°-128° C., was obtained by recrystallisation of an aliquot from cyclohexane.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:22][CH2:23][C:24]([O:26]C)=[O:25]>C(Cl)Cl>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCBr
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.5 g, 7.8 mmol) suspended in 16 mL of CH2Cl2. To this suspension was added triethylamine (2.1 mL, 15.3 mmol) followed by methyl 3-bromopropionate (1.0 mL, 9.2 mmol). The reaction was stirred at room temperature for 4 h and at reflux for 2 h. The reaction mixture was washed with water, 1N HCl (2×20 mL), 1N NaOH (2×20 mL) and Brine (1×20 mL). The organic layer was separated, dried over Na2SO4, filtered; and solvent was removed under reduced pressure. To the crude product was added 2N NaOH (15 mL). The mixture was stirred at reflux for 1 h. The reaction mixture was washed with CH2Cl2 (3×20 mL) and neutralized with concentrated HCl. The aqueous solution was concentrated to dryness under reduced pressure, to give a solid residue. Sodium chloride in the residue was removed in the following way (three repeats): dissolving the residue in a minimum amount of water, treating the aqueous solution with acetone, removing the resultant solid material by filtration, and concentrate the filtrate to dryness under reduced pressure. This allowed the isolation of compound Q (159.4 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[S:8][C:9](C(O)=O)=[CH:10][C:6]=2[CH:5]=1.N12CCCN=C1CCCCC2>CC(N(C)C)=O.Cl>[F:17][C:2]([F:1])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1
Reactant: O=C(O)c1cc2cc(OC(F)(F)F)ccc2s1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: FC(F)(F)Oc1ccc2sccc2c1
Temperature: 200 °C
Yield: 31.1 %

Procedure:
A mixture of 5-trifluoromethoxy-benzo[b]thiophene-2-carboxylic acid (2.00 g, 7.63 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5.0 mL, 32 mmol) in DMA (12 mL) was heated via microwave irradiation at 200° C. for 1 h. The reaction was cooled to rt, diluted with HCl (1 N aq., 15 mL) and extracted with EtOAc (15 mL). The organic layer was washed with water (10 mL), dried (Na2SO4) and concentrated. The residue was taken up in Et2O (25 mL) and washed with water (25 mL). The aqueous layer was extracted with Et2O (10 mL×2). The combined Et2O layers were dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (518 mg, 31%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([CH2:14][C:15]2[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([F:26])=[N:9][C:10]=2[NH2:25].[C:27]([S:31](Cl)=[O:32])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[NH2:25][C:10]1[N:9]=[C:8]([F:26])[N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([CH2:14][C:15]1[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:32]
Reactant: NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Reactant: CC(C)(C)S(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)S(=O)NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a solution of 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (80 mg, 0.17 mmol) in DCM (3 mL) was added t-butylsulfinyl chloride (28 uL, 0.25 mmol) and triethylamine (30 uL, 0.25 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield WS60 as a white solid (45 mg, 46%). 1H NMR (500 MHz, CDCl3): δ 7.28 (s, 1H), 6.62 (s, 1H), 6.04 (brs, 2H), 5.97 (s, 2H), 4.60 (t, J=6.5 Hz, 1H), 4.24 (s, 2H), 4.20 (m, 1H), 4.09 (m, 1H), 3.13 (m, 1H), 2.97 (m, 1H), 2.00 (m, 1H), 1.85 (m, 1H), 1.27 (s, 9H). HRMS (ESI) m/z [M+H]+ calcd. for C20H25IFN6O3S, 575.0725. found 575.0738.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH:14]=[O:15])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[BH4-].[Na+].O>CO>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:14][OH:15])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: COc1ccc(C=O)cc1OS(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CO)cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 17.5 °C
Yield: 97 %

Procedure:
To a cooled solution of 3-[(p-Toluenesulfonyl)oxy]-4-methoxybenzaldehyde 21 (9.0 g, 29 mmol) in methanol (25 mL) was added sodium borohydride (0.55 g, 14.5 mmol) in methanol (2.5 mL) over a period of 5-10 min maintaining the temperature around 15-20° C. The reaction mixture was maintained at that temperature for further 30 min and checked TLC for completion of the reaction. Water was added to the reaction mixture and the solid formed was filtered, washed with water and dried to afford 22. Yield: 97%; white solid mp 88-90° C. 1H NMR: δ 2.41 (s, 3H, CH3), 3.59 (s, 3H, OCH3), 4.57 (s, 2H, CH2), 6.80-7.79 (m, 7H, Ar—H). Anal. Calcd for C15H16O5S: C, 58.43, H, 5.23. Found: C, 58.49, H, 5.19.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]4[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=4)[CH2:25][CH2:26]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Product: O=C(c1ccc2[nH]ccc2c1)N1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
In the manner described in Example 24, indole-5-carboxylic acid (100 mg, 0.62 mmol) and 1-[2-(4-nitrophenyl)ethyl]piperazine (151 mg, 0.64 mmol) gave, after purification by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 ; 95:5:0.5 and trituration with hexane/EtOAc, the piperazine (38 mg, 16%), mp 204°-206° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][CH:33]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:33]=[N:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FC(F)(F)c1ccc(Br)cn1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)nc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 5-bromo-2-(trifluoromethyl)pyridine.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.[Br:26][C:27]1[CH:28]=[N:29][NH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:26][C:27]1[CH:28]=[N:29][N:30]([C:2]2[C:7]([Cl:8])=[CH:6][N:5]=[C:4]3[N:9]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:10]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)=[CH:11][C:3]=23)[CH:31]=1
Reactant: Brc1cn[nH]c1
Reactant: Cn1cc(-c2cc3c(Cl)c(Cl)cnc3n2COCC[Si](C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2cc3c(-n4cc(Br)cn4)c(Cl)cnc3n2COCC[Si](C)(C)C)cn1
Temperature: 150 °C

Procedure:
A solution of Example 113E (0.194 g, 0.488 mmol) and 4-bromo-1H-pyrazole (0.115 g, 0.781 mmol) in 1-methyl-2-pyrrolidinone (0.8 mL) was treated with potassium carbonate (0.169 g, 1.22 mmol), and the reaction was heated at 150° C. for 2.5 hours. The reaction was cooled to ambient temperature, and partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of 0% to 1% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 509.0 [M+H]+.
Reaction SMILES: [CH2:1](Cl)[C:2](=[CH2:4])[CH3:3].[C:6]1([C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9])[OH:7]>>[CH2:1]([O:7][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[OH:9])[C:2](=[CH2:4])[CH3:3]
Reactant: C=C(C)CCl
Reactant: Oc1ccccc1O
Product: C=C(C)COc1ccccc1O
Yield: 68 %

Procedure:
These Examples A-D show that if the alkaline reagent used is sodium hydroxide or potassium hydroxide, an increase in the amount of methallyl chloride used improves the degree of conversion of the pyrocatechol as well as the yield of monoether, but results in a substantial formation of diether and of benzene ring alkylation products. Thus, if reference is made to Examples B and D, the use of one mol of methallyl chloride per mol of pyrocatechol, results in monoether/diether molar ratios of, respectively, 1.8 in Example B and 3.8 in Example D. If reference is now made to Examples 1 to 14 according to the present Patent Application, it will be seen that according to the process claimed, it is possible to use large amounts of methallyl chloride without reducing the selectivity of the reaction. Thus, according to Example 1, the use of 1.5 mols of methallyl chloride per mol of pyrocatechol makes it possible to achieve a molar ratio of monoether/diether of 7.6, whilst having a yield of 68% of o-methallyloxyphenol relative to the pyrocatechol starting material, and a content of benzene nucleus alkylation products of 4% relative to pyrocatechol converted.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)(=[O:3])[CH3:2].C(OO)(=[O:14])C>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N+:6]=1[O-:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OO
Reactant: CC(=O)Nc1cccc(Br)n1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(Br)[n+]1[O-]
Reaction time: 19 h
Yield: 83 %

Procedure:
More specifically, the mercapto pyridine-1-oxide derivatives of the instant invention are prepared from known starting materials. 2-amino-6-bromopyridine which may be prepared by hydrogen bromide induced cyclization of 3-hydroxyglutaronitriles, a method described in U.S. Pat. No. 3,096,337, or by any other known process, is dissolved in an excess amount of acetic anhydride and heated at 70° C. for 45 minutes and the excess acetic anhydride is hydrolyzed by the addition of 300 ml. water, to give a substantially quantitative yield (95%) of 2-acetamido-6-bromopyridine which has a melting point of 159.2°-160.0° C. The 2-acetamido-6-bromopyridine is oxidized by heating a solution thereof in glacial acetic acid with an excess of peracetic acid at 70° C. for 2 hours and at 55° C. for 19 hours. The reaction mixture is diluted with 1600 ml. water and concentrated in vacuum, unreacted material removed by filtration, and the solvent evaporated from the filtrate, giving an 83% yield of impure 2-acetamido-6-bromopyridine-1-oxide which is purified and recrystallized from 2-propanol to yield fine white needles having a melting point of 180.0°-180.5° C. The mercapto derivative of 2-acetamido-6-bromopyridine-1-oxide may be prepared by reaction with an excess of sodium hydrosulfide (1 M NaSH) in an aqueous-ethanol medium while stirring for 5 hours at 60° C. and overnight at room temperature, adding concentrated hydrochloric acid dropwise to the cold yellow solution and collecting the light yellow solid by filtration, purifying by recrystallization from 2-propanol and obtaining pale yellow crystals having a melting point of 172.8°-173.5° C. A 79% yield of 2-acetamido-6-mercaptopyridine-1-oxide is obtained with the aforedefined process.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1)=[O:3].[C:12](Cl)(=[O:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc(F)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(C)=O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round, bottom flask was added 3-amino-4-fluoroacetophenone (Method 64, 1 g, 6.54 mmol) in DMF (15 ml), followed by the addition of acetyl chloride (0.56 ml, 7.84 mmol) and DIEA (2.3 ml, 13.08 mmol). The solution was set to stir at room temperature. The reaction appeared complete by TLC after 30 min. The reaction was then quenched with water and partitioned with EtOAc. The layers were cut, followed by an additional wash of the aqueous with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue obtained (1.17 g), was used directly in the next step. 1H NMR (CDCl3) δ 8.94 (d, J=7.54 Hz, 1H) 7.71 (d, 1H) 7.43 (s, 1H) 7.15 (s, 1H) 2.56-2.60 (m, 3H) 2.21-2.28 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.[OH:22][C@H:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24](O)=[O:25]>C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:24](=[O:25])[C@H:23]([OH:22])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[C@@H](O)C(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](O)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
The title compound was prepared from N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (hydrochloride salt, Example 26, Step B, 55 mg, 0.16mmol) and (2R)-hydroxy-3,3-dimethylbutyric acid (22 mg, 0.16 mmol) essentially according to the EDC coupling procedure described in Example 27, Step C (without the deprotection step). The mixture was stirred for 18 h at ambient temperature and was then concentrated in vacuo. The residue was purified directly by semi-preparative HPLC using a Waters Xterra RP8 column (1.9 cm×30 cm) using a 30 minute gradient of 95/5-water/MeCN to 100% MeCN with 0.1% TFA as the mobile phase at a flow rate of 20 mL/min. The product-containing fractions were concentrated in vacuo to afford the title compound as a white crystalline solid (62 mg). HPLC RT=2.86 min (Method A); LCMS m/z=421.3; 1H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.51 (br m, 1H), 7.44 (dd, J=2.2, 8.4 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 4.5 (dd, J=3.8, 8.6 Hz, 1H) 4.25 (d, J=5.3 Hz, 1H), 4.2 (m, 1H), 4.15 (s, 1H) 3.69 (m, 1H), 3.57 (m, 1H), 2.73 (br s, 1H), 1.8–2.1 (m, 4H), 1.0 (s, 9H)).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:29][CH:30]([F:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[F:40][CH:30]([F:29])[C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:16][CH:15]([N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: FC(F)c1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1
Product: FC(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1

Procedure:
4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine from Example 126 (0.07 g) was reacted with 2-(difluoromethyl)-1H-benzo[d]imidazole via General Procedure D to produce 10.7 mg of 172 following reverse phase HPLC purification. MS (Q1) 537.2 (M)+