Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:27]1[N:32]=[C:31](B(O)O)[CH:30]=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[N:32]=[C:31]([C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:9][C:4]=2[C:3]([OH:2])=[O:24])[CH:30]=[CH:29][CH:28]=1)#[N:26]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: N#Cc1cccc(B(O)O)n1
Product: N#Cc1cccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)n1
Yield: 15.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 6-cyanopyridine-2-boronic acid (available from CombiPhos Catalysts, Inc.; 59 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2-(6-cyano-pyridin-2-yl)-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid (14 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 8.24-8.32 (m, 1H), 8.00-8.16 (m, 3H), 7.73-7.88 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]3[O:20][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[O:13]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Yield: 69.7 %

Procedure:
A mixture of 4-(4-chlorophenyl)benzaldehyde (15.0 g.), 2-hydroxy-2-methylpropionic acid (10.0 g.) and p-toluenesulphonic acid monohydrate (0.2 g.) was heated in toluene (200 ml.) under reflux for 6 hours with continuous removal of water by azeotropic distillation. The solution was then cooled, washed with 10% w/v sodium hydrogen carbonate solution (100 ml.) and then with water (2×100 ml.) before it was dried (Na2SO4). The dried toluene solution was filtered and evaporated to give 2-[4-(4-chlorophenyl)phenyl]-5,5-dimethyl-1,3-dioxolan-4-one (14.6 g.), m.p. 108°-110° C. (after recrystallisation from cyclohexane and then from toluene).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:51][N:17]3[C:18](=[O:50])[C@@H:19]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH:25]=[CH:26][C@@H:27]4[CH2:32][C@@:28]4([C:33](=[O:41])[NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:37])=[O:36])[NH:29][C:30](=[O:31])[C@@H:16]3[CH2:15]1)=[O:12])[CH2:6]2.[H][H].O.S([O-])(O)(=O)=O.[K+]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:51][N:17]3[C:18](=[O:50])[C@@H:19]([NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]4[CH2:32][C@@:28]4([C:33](=[O:41])[NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:36])=[O:37])[NH:29][C:30](=[O:31])[C@@H:16]3[CH2:15]1)=[O:12])[CH2:6]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCOCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCOCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCOCCCC[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Reaction time: 16 h
Yield: 38.1 %

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate (0.037 g, 0.050 mmol) and Rh/Al (5%) (0.021 g, 0.010 mmol) in Ethyl acetate (5 mL) was charged with 1 atmosphere of hydrogen and stirred for 16 hrs. Water (3 mL) and saturated potassium hydrogen sulfate (3 mL) was added and stirred for 10 minutes. The organic phase was separated and aqueous phase extracted with ethyl acetate (10 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:2) to give (2R,6S,13aR,14aR,16aS)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxohexadecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.014 g, 38%). MS: Calcd.: 735; Found: [M+H]+ 736. 1H NMR (400 MHz, d6-DMSO) δ11.08 (s, 1H), 8.79 (b, 1H), 7.34 (m, 1H), 7.10-7.20 (m, 3H), 5.28 (m, 1H), 4.66 (s, 4H), 4.41 (m, 1H), 4.20 (m, 1H), 3.94 (m, 1H), 3.74 (m, 1H), 3.42-3.47 (m, 2H), 2.97 (m, 1H), 0.79-2.38 (m, 28H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:11]O)=[N:5][CH:6]=[C:7]([O:9][CH3:10])[N:8]=1.O=S(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][CH2:11][C:4]1[C:3]([O:2][CH3:1])=[N:8][C:7]([O:9][CH3:10])=[CH:6][N:5]=1
Reactant: COc1cnc(CO)c(OC)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cnc(CCl)c(OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3,5-dimethoxy-pyrazin-2-yl)-methanol (100 mg, 0.59 mmol) in DCM (5 mL) was added SOCl2 (5 eq) at room temperature. The mixture is stirred at room temperature for an additional one hour. Solvent and volatile materials are removed in vacuo to dryness to give 110 mg of 2-chloromethyl-3,5-dimethoxy-pyrazine as an oil.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][N:7]([CH3:20])[C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Reaction time: 72 h
Yield: 61.2 %

Procedure:
To a mixture of 3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione (50 mg, 0.137 mmol) and potassium carbonate (76 mg, 0.548 mmol) in DMF (2 mL) was added iodomethane (26 μL, 0.411 mmol) at RT. After 3 days, the reaction mixture was partitioned between ethyl acetate and water. The resultant biphasic mixture was separated, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was crystallised from ethyl acetate to give the title compound (31.8 mg, 61%) as a cream solid. The mother liquors were evaporated, the residue was dissolved in DCM and subjected to flash chromatography (SiO2, gradient 70 to 100% ethyl acetate in cyclohexane) to afford a further quantity of the title compound (17.6 mg, 34%). LCMS (Method A): RT=3.78 min, [M+H]+=380.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.C(O)C.[Cl-].[NH4+]>[Fe].O>[S:11]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1)[C:12]#[N:13]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#CSc1ccc(N)c(N)c1
Reaction time: 0.25 h
Yield: 74 %

Procedure:
To a suspension of 2-nitro-4-thiocyanato-aniline, 22.3 g. of powdered iron, 50 ml. of 96% ethanol and 50 ml. of water a solution of 2.2 g. of ammonium chloride and 15 ml. of water is added dropwise under stirring at the boiling point of the mixture. Stirring is continued for a further 15 minutes, whereupon the reaction mixture is filtered until warm. To the filtrate 250 ml. of water are added. After cooling the precipitated crystals are filtered off. Thus 12.2 g. of 4-thiocyanato-1,2-diaminobenzene are obtained. Yield: 74%. M.p.: 108°-110° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:17](=[O:19])[CH3:18])[C:6]=2[CH2:5]1)[CH2:2][CH3:3].[N+:20]([O-])([O-:22])=[O:21].[K+]>OS(O)(=O)=O>[N+:20]([C:10]1[CH:9]=[C:8]2[C:13]([C:14]3[CH2:15][CH2:16][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]=3[N:7]2[C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])[O-]
Reactant: CCCN1CCc2c(n(C(C)=O)c3ccccc23)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCN1CCc2c(n(C(C)=O)c3cc([N+](=O)[O-])ccc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To 1-(2-propyl-1,2,3,4-tetrahydro-beta-carbolin-9-yl)-ethanone (1.05 g, 4.1 mmol) in conc. H2SO4 was added KNO3 (435 mg, 4.3 mmol) in small portions at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for an additional 30 minutes. The reaction mixture was poured onto 250 ml of ice and extracted once with ethyl acetate. The aqueous phase was made alkaline and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness to yield 1.2 g of crude product (70% purity).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][N:11]2[CH2:20][CH:19]3[CH2:21][O:22][CH2:23][CH2:24][N:18]3[C:17]3[N:16]=[C:15]([Cl:25])[N:14]=[CH:13][C:12]2=3)[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:15]1[N:14]=[CH:13][C:12]2[N:11]([CH2:10][C:4]3[CH:3]=[C:2]([CH3:26])[CH:9]=[CH:8][C:5]=3[C:6]#[N:7])[CH2:20][CH:19]3[CH2:21][O:22][CH2:23][CH2:24][N:18]3[C:17]=2[N:16]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Br)cc1CN1CC2COCCN2c2nc(Cl)ncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(CN2CC3COCCN3c3nc(Cl)ncc32)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a 20 mL vial were added 4-bromo-2-((2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzonitrile (105 mg, 0.250 mmol), potassium carbonate (69.0 mg, 0.499 mmol), PdCl2(dppf) (18.26 mg, 0.025 mmol), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.042 mL, 0.300 mmol) in dioxane (2 mL) and water (0.4 mL). The resulting brown suspension was stirred overnight at 100° C. The reaction mixture was subsequently diluted with EtOAc and washed with saturated NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (SiO2, 4 g column, 2:8 to 8:2 EtOAc/Hexane gradient) to give the title compound as a tan solid (52 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3 H), 2.92-3.08 (m, 3 H), 3.10-3.20 (m, 2 H), 3.24-3.32 (m, 2 H), 3.40-3.52 (m, 2 H), 3.62-3.75 (m, 2 H), 3.81-3.90 (m, 2 H), 3.91-4.00 (m, 2 H), 4.21-4.31 (m, 2 H), 4.41-4.63 (m, 3 H), 7.30-7.38 (m, 2 H), 7.38-7.55 (m, 3 H), 7.67-7.73 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H18ClN5O, 356.1; found 356.1.
Reaction SMILES: Br[CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3]>C1C=CC=CC=1>[CH3:3][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[C:4]1[CH:13]=[CH:12][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(C)Br)cc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C(C)c2ccccc2)cc1

Procedure:
In the same manner as in Reference Example 25, by using methyl 4-(α-bromoethyl)benzoate and benzene, there was prepared the title compound.
Reaction SMILES: C[O:2][C:3]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5](=O)[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:9][C:7]1([CH3:10])[CH2:8][C:3](=[O:2])[CH:4]=[CH:5][CH2:6]1
Reactant: COC1=CC(=O)CC(C)(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CC=CC(=O)C1
Reaction time: 4 h

Procedure:
A solution of 3-methoxy-5,5-dimethyl-cyclohex-2-enone (80 g, 0.52 mol) in anhydrous tetrahydrofuran (270 mL) was treated dropwise with a 1 M solution of LiAlH4 in tetrahydrofuran (182 mL), under argon atmosphere and keeping the temperature of the reaction between 0° C. and 5° C. The temperature was allowed to rise to 25° C. and the mixture was stirred for 4 hours. The resulting slurry was cooled with an ice bath, quenched with ethyl acetate (30 mL) and poured with caution into a cooled 2 M H2SO4 solution. The aqueous solution was then extracted with diethyl ether (300 mL×3), dried on Na2SO4 and evaporated under reduced pressure to remove most of the solvent. The crude material contained the title compound as a low boiling point oil that was used in the next step without further purification.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>ClCCl>[Si:20]([O:10][CH2:9][CH2:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: OCCNc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCNc1ccccc1
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To a stirred solution of 2-(phenylamino)ethanol (10 g, 72.9 mmol, Eq: 1.00) in dichloromethane (200 ml) were added diisopropylethylamine (13.2 g, 17.8 ml, 102 mmol, Eq: 1.4) followed by tert-butyldimethylsilyl chloride (11.0 g, 72.9 mmol, Eq: 1.00) at room temperature under a nitrogen atmosphere. The resulting solution was stirred for 16 hrs and then it was poured into water (200 ml) and the organic layer was separated, washed with brine, dried (MgSO4), concentrated, and chromatographed (silica gel, gradient 0 to 10% ethyl acetate-hexane) to obtain N-(2-(tert-butyldimethylsilyloxy)ethyl)aniline (46) (8.45 g, 33.6 mmol, 46.1% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[Li+].[CH3:9][CH:10]([N-]C(C)C)C.C(I)C.Cl>C1COCC1.C1COCC1.CCCCCC>[CH2:9]([CH:3]([C:2]([CH3:7])=[CH2:1])[C:4]([OH:6])=[O:5])[CH3:10]
Reactant: CC(C)=CC(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(C)C(CC)C(=O)O
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 120.2 %

Procedure:
A solution of 3,3-dimethylacrylic acid (2.00 g, 20 mmol) in THF (30 mL) was added dropwise to a solution of LDA (44 mmol) in THF/hexane (60 mL) at −78 ° C. After warming to −10 ° C. and stirring for 20 min, the reaction was recooled to −78 ° C. and a solution of ethyl iodide (6.86 g, 44 mmol)) in THF (30 mL) was added. The reaction was allowed to warm to room temperature overnight. To the resulting dark orange solution was added 1 M HCl until acidic. The organic layer was separated, washed with H2O and brine, dried (MgSO4), filtered and concentrated to yield a brown oil of 2-ethyl-3-methylbut-3-enoic acid (3.08g), which was used crude in the next reaction. To reduce the acid group the crude product was dissolved in THF (70 mL) and cooled to 0° C. To this was added LiAlH4 (2280 mg, 60 mmol). Workup gave 2.7 g of a pale yellow oil, which was purified by flash chromatography (silica gel, 10% EtOAC in pet. ether) to give 1.70 g of 2-ethyl-3-methylbut-3-en-1-ol as an oil. The alcohol (560 mg, 4.91 mmol) was converted into a mesylate by dissolving in DCM (25 mL) at 0 ° C., then adding MsCl (675 mg, 5.9 mmol) followed by Et3N (595 mg, 5.9 mmol). After 30 min the reaction was partitioned between DCM and 0.1 N HCl, the aqueous layer extracted with DCM (2×), and the organic fractions combined and washed with brine, filtered and concentrated to give 200 mg of a pale yellow oil. The crude mesylate (4.91 mmol) was dissolved in acetonitrile (20 mL) and NaN3 (957 mg, 14.7 mmol) was added. After 1 h DMF (6.5 mL) was added and the reaction heated to reflux for 3 h, then cooled. EtOAc (40 mL) and NaHCO3 solution were added and the organic layer was washed with H2O (2×), brine (1×) and dried, then filtered to give a pale yellow solution of 3-(azidomethyl)-2-methylpent-1-ene that was used crude in the next reaction. A suspension of the azide (4.91 mmol) in 50 mL EtOAC was hydrogenated at 40 psi over Lindlar catalyst (460 mg) for 16 h, then filtered through Celite to leave a colourless solution. Flash chromatography (silica gel, 1-5% MeOH in DCM) produced 120 mg of pure amine 57, with a further 95 mg of impure material
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:5]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([OH:27])=[C:17]([C:22]([O:24]CC)=[O:23])[CH:18]=3)[C:6]=2[O:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)#[N:2].O.[OH-].[Li+].[OH-].[Li+].[Cl-].[Na+]>C1COCC1.C(O)(=O)C.O>[C:1]([C:3]1[CH:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:5]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([OH:27])=[C:17]([C:22]([OH:24])=[O:23])[CH:18]=3)[C:6]=2[O:7][C:8]=1[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13]1)#[N:2]
Reactant: CCOC(=O)c1cc2ccc3c(c2cc1O)OC(n1cccc1)=C(C#N)C3c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: N#CC1=C(n2cccc2)Oc2c(ccc3cc(C(=O)O)c(O)cc23)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyl 3-cyano-9-hydroxy-4-(3-nitrophenyl)-2-(1-pyrrolyl)-4H-naphtho[1,2-b]pyran-8-carboxylate (1.91 g) was dissolved in THF (10 ml). Water (1 ml) and lithium hydroxide monohydrate (180 mg) were added and the solution stirred at room temperature for 45 minutes. A further quantity of lithium hydroxide (180 mg) was added and the solution heated under reflux for one hour. The solution was poured into water (100 ml) and glacial acetic acid (50 ml) added. Solid sodium chloride was added until no more would dissolve, then the mixture extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried over magnesium sulphate, then solvent removed under reduced pressure to give a brown-yellow solid. This was triturated with ether (10 ml), the solid collected by filtration and dried to yield 3-cyano-9-hydroxy-4-(3-nitrophenyl)-2-(1-pyrrolyl)-4H -naphtho[1,2-b]pyran-8-carboxylic acid, m.p. >230° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][O:11]C(OCC)C.C([Li])CCC.C[O:23][B:24](OC)OC.Cl>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[B:24]([OH:23])[O:11][CH2:10][C:3]=2[CH:4]=1
Reactant: CCOC(C)OCc1cc(OC)ccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)COB2O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
Dissolve 1-bromo-2-(1-ethoxy-ethoxymethyl)-4-methoxy-benzene (3.0 g, 10.3 mmol)in THF (100 mL) and cool to −78° C. Add 2.5M butyllithium in hexanes (4.6 mL, 11.4 mmol), dropwise and stir for 15 min. Add trimethylborate (2.1 g, 20.6 mmol) to the reaction mixture and warm to room temperature. Add 1N HCl (100 mL) and stir at room temperature for 2 hours. Extract three times with methylene chloride, dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo to yield a crude product. Triturate with methylene chloride/hexanes to yield 680 mg (40%) of the title compound. 1H NMR (CDCl3) δ 7.65 (d, J=8.2 Hz, 1H), 6.93 (dd, J=8.2, 2.1 Hz, 1H), 6.85 (d, J=1.4 Hz, 1H), 5.06 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][CH2:31][OH:32])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(NC(C)C)(C)C>C(Cl)Cl>[CH3:39][S:40]([O:32][CH2:31][CH2:30][O:29][C:28]1[CH:27]=[C:26]([F:36])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:34]([F:35])[CH:33]=1)(=[O:42])=[O:41]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCOS(C)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
To 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanol (270 mg, 0.48 mmol, 1.0 eq) in DCM (2.5 mL) was added methanesulfonyl chloride (0.1 mL, 1.44 mmol, 3.0 eq), followed by diisopropylamine (0.25 mL, 1.44 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 45 min at which time LCMS showed complete consumption of starting material. Aqueous work up (EtOAc and water) followed by purification (column chromatography, 0 to 80% EtOAc/Hex) provided 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethyl methanesulfonate (230 mg, 75%) as a white foam. MS (EI) m/z 462 (MH+).
Reaction SMILES: [OH-].[K+].[C:3]([NH:7][C:8]([C:10]1[S:14][C:13]([S:15][CH3:16])=[N:12][C:11]=1[C:17]([O:19]CC)=[O:18])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.O.C(O)C>[C:3]([NH:7][C:8]([C:10]1[S:14][C:13]([S:15][CH3:16])=[N:12][C:11]=1[C:17]([OH:19])=[O:18])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1nc(SC)sc1C(=O)NC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc(C(=O)O)c(C(=O)NC(C)(C)C)s1

Procedure:
0.82 g (14.6 mmol) of potassium hydroxide in 10 ml of water was added to a solution of 4.00 g (13.2 mmol) of 4-ethoxycarbonyl-2-methylthiothiazole-5-carboxylic acid-tert-butylamide in 50 ml of water/ethanol (2:1), and the mixture was refluxed for 2 hours. The solvent mixture was then removed under reduced pressure and the residue was taken up in 50 ml of water and acidified with concentrated hydrochloric acid. The precipitated product was filtered off and dried.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:6]=[C:7]([C:9]#[C:10][Si](C)(C)C)[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:9]([C:7]1[CH:6]=[C:5]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:4]=[C:3]([C:2]([F:31])([F:32])[F:1])[CH:8]=1)#[CH:10]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(C#C[Si](C)(C)C)cc(C(F)(F)F)c3)cs2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(-c2csc(Cn3cc(C(=O)OCC)cn3)n2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (20 mL) of the compound (2.1 g, 4.4 mmol) obtained in Example 98a in tetrahydrofuran was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 6.5 mL, 6.5 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (940 mg, 53%) as orange crystals.