Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:33][C:29]4([CH3:28])[CH2:32][O:31][CH2:30]4)=[O:24])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: CC1(N)COC1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Solvent: CCOC(C)=O
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3(C)COC3)cc2)cn1
Yield: 64 %

Procedure:
As described for example 3b, 4-{4-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-imidazol-1-yl}-benzoic acid (75 mg, 0.21 mmol) was converted, using 3-methyl-3-oxetanamine instead of isopropylamine, to the title compound (57 mg, 64%) which was obtained as a white solid after trituration from ethyl acetate. MS: m/e=433.4 [M+H]+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][CH2:22]3)[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:22]1[C:23]2[C:19](=[C:18]([O:17][CH:14]3[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]3)[CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: O=C(Cl)Cl
Reactant: c1ccc(CN2CCC(Oc3cccc4c3CCC4)C2)cc1
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2cccc3c2CCC3)C1
Reaction time: 18 h
Yield: 91 %

Procedure:
To a stirred solution of 6.9 g (0.07 mole) of phosgene in 100 ml of anhydrous benzene under nitrogen gas and cooled at 10° C. was added dropwise a solution of 18.13 g (0.062 mole) of 1-benzyl-3-(4-indanyloxy)pyrrolidine in 50 ml of dry benzene. After stirring for 18 hr, the slightly turbid reaction mixture was filtered through celite. The filtrate was washed with 50 ml of ice-water, dried over magnesium sulfate and concentrated on a rotary evaporator. The solid residue was triturated with boiling isopropyl ether. Fifteen grams of crude product was obtained by filtering the mixture. Recrystallization from a mixture of benzene and 30/60 petroleum ether gave 13.1 g of cream colored solid, m.p. 128°-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[CH3:24][N:25]([CH3:40])[C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[C:31]2[S:36]([NH2:39])(=[O:38])=[O:37]>>[Br:23][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:13]=1)[C:5]([C:30]1[CH:29]=[CH:28][C:27]2[C:32](=[CH:33][CH:34]=[CH:35][C:26]=2[N:25]([CH3:24])[CH3:40])[C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37])=[O:6]
Reactant: CN(C)c1cccc2c(S(N)(=O)=O)cccc12
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3ccc4c(N(C)C)cccc4c3S(N)(=O)=O)cc2Br)ccc1O
Yield: 34.5 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 5-dimethylamino-1-naphthalenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 8 mg (34%) of the title compound.
Reaction SMILES: Cl.[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:33]/[OH:34])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48]>CN(C)C=O>[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:33]/[O:34][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COCCOCCBr
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCCOCCOC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
In 50 ml of dimethylformamide is dissolved 7.41 g of ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate hydrochloride and with stirring at room temperature, 4.15 g of potassium carbonate and 2.75 g of 1-bromo-2-(2-methoxyethoxy)ethane are added. The mixture is stirred for 48 hours, after which it is poured into 500 ml of ice water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (150 g) column and elution is carried out with hexane-ethyl acetate (1:1). The fractions rich in the desired compound are pooled and concentrated under reduced pressure to give 4.84 g of ethyl 2-(2-tritylaminothiazol4-yl)-(Z)-2-[2-(2-methoxyethoxy)ethoxyimino]acetate as a yellow foamy product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6](=[O:28])[C:5]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[N:29]([CH3:31])[CH3:30].[H-].[Na+].[CH3:41]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([N:20]([CH3:41])[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[C:6](=[O:28])[C:5]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[N:29]([CH3:30])[CH3:31]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3Cl)(N(C)C)c3cc(Cl)ccc32)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)N(C)c1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3Cl)(N(C)C)c3cc(Cl)ccc32)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.420 g of the compound obtained in EXAMPLE 30 in 7 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.027 g of sodium hydride as an 80% dispersion in oil is added. After stirring for 30 minutes, 0.05 ml of methyl iodide is added and the reaction mixture is stirred for 10 minutes. It is poured into water, extracted with AcOEt, washed with water, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=0.211 g. M.p.=145°-148° C.
Reaction SMILES: [CH2:1]([C:7](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[Zn].C(O)(=O)C>[CH2:1]([C:7]([CH:8]([OH:9])[CH:8]([OH:9])[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCC(=Cc1ccccc1)C(O)C(O)C(=Cc1ccccc1)CCCCCC

Procedure:
In a fashion similar to that described in Example 1, α-hexyl-cinnamaidehyde was treated with zinc and acetic acid to provide 2,5-dihexyl-1,6-diphenyl-1,5-hexadiene-3,4-diol.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH:17]C(=O)C1C=CC=CC=1)=[S:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+].CO>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH2:17])=[S:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(=S)Nc1ccccc1Oc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=S)Nc1ccccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Thus produced 1-(2-phenoxyphenyl)-3-benzoylthiourea was dissolved in a mixture of 10% aqueous sodium hydroxide (660 ml) and methanol (530 ml) at 50° C. The reaction mixture was stirred for 30 minutes at 50° C. and then cooled with ice to give crystals, which were separated by filtration, washed with water and dried to give 1-(2-phenoxyphenyl)thiourea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[N:12]([CH2:11][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=1)([CH3:23])[CH3:24]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)c(OC)c1
Product: COc1ccc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)c(OC)c1
Yield: 93.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(2,4-dimethoxyphenyl)methyl](4-isopropylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (1.2 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)urea (1.6 g) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.Cl>CC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:11][S:8]([C:6]2[O:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)(=[O:9])=[O:10])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCc1ccc(S(N)(=O)=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 5-ethyl-2-furansulfonamide (4.5 g, 25.7 mmole) in 40 ml of acetone was added aqueous sodium hydroxide (25.7 ml of 1N, 25.7 mmole) followed by a solution of 4-chlorophenylisocyanate (3.9 g, 25.7 mmole) dissolved in 40 ml of acetone. The reaction was stirred at room temperature overnight and filtered through a plug of celite. The filtrate was acidified with hydrochloric acid (25.7 ml of 1N, 25.7 mmole) and the resulting precipitate filtered to produce 8.3 g of solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][OH:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1.CCN(CC)CC.C(Cl)Cl.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][O:13][S:55]([CH3:54])(=[O:57])=[O:56])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COC(COS(C)(=O)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 0.236 mmol) and Et3N (0.099 mL, 0.709 mmol) in DCM (3 mL, 46.6 mmol) at 0 C was added Methanesulfonyl chloride (0.037 mL, 0.473 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was cooled to 0 , quenched by addition of saturated NaHCO3 and diluted with ether, the layers were separated and the ether layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by Biotage LC (30% EtOAc/Hex) to give 155 mg of title product as white foam (92% yield). LC/MS (HPLC method 3): tR=4.15 min, 712.3(MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[CH:16][C:17](C)=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[C:21]1C=C(C=CC=1C)N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[CH:16][CH:17]=[C:18]([CH3:21])[N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc2c(Nc3ccc(C)c(O)c3)ncnn2c1
Reactant: Cc1ccc(N)cc1O
Product: Cc1ccc(Nc2ncnn3c(C)ccc23)cc1O

Procedure:
Example 11 was prepared as a white solid in 30% overall yield from Compound E using the 2 step sequence of Compound A of Example 1 and Compound B of Example 1, using 3-hydroxy-4-methylaniline. The product was purified by flash chromatography on silica with 25% ethyl acetate/hexanes. (M+H)+255.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH:21]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH:11]([F:12])[F:13])[CH:5]=[O:6])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OC2CCCC2)c1
Temperature: 50 °C
Yield: 91.1 %

Procedure:
To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde 2.9 g, 15 mmol) and powdered potassium carbonate (3.2 g, 23 mmol) in dimethylformamide (15 mL) under an argon atmosphere was added bromocyclopentane (2.5 mL, 23 mmol) and the mixture was stirred and heated at 50° C. for 1 h and at 80°-85° C. 1.5 h. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic extract was washed three times with water, was dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 20-30% ether/hexanes, provided a yellow solid (3.5 g, 89%).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([C:3]([N:2]([CH3:28])[CH3:1])=[O:4])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:33][N:32]=1
Reactant: CN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)N(C)C)CC4)cc3n2)c(OC)n1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine in General Procedure A. Purification on silica yielded 109. NMR (CDCl3): 2.48-2.51 (m, 4H, 2×CH2), 2.76 (s, 6H, 2×CH3), 3.21-3.24 (m, 4H, 2×CH2), 3.77-3.80 (m, 4H, 2×CH2), 3.93-3.96 (m, 4H, 2×CH2), 3.99 (s, 3H, CH3), 4.01 (s, 3H, CH3), 7.25 (s, H, ArH), 8.83 (s, H, ArH). MS: (ESI+): MH+=529.35
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:14]1([C:17]2[NH:18][CH:19]=[C:20]([C:22]3[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=3)[CH:27]=O)[N:21]=2)[CH2:16][CH2:15]1.C[O-].[Li+]>CN(C)C=O>[CH:14]1([C:17]2[NH:18][CH:19]=[C:20]([C:22]3[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[C:26](/[CH:27]=[CH:2]/[C:1]([C:4]4[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=4)=[O:3])[CH:29]=3)[N:21]=2)[CH2:15][CH2:16]1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC)c(-c2c[nH]c(C3CC3)n2)cc1C=O
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2c[nH]c(C3CC3)n2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-acetyl-benzenesulfonamide (Ex-26A, 0.12 g, 0.59 mmol) and 5-(2-cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-benzaldehyde (Ex-105B, 0.16 g, 0.59 mmol) in N,N-dimethylformamide (16 mL) was added lithium methoxide (1.0M in methanol, 2.4 mL, 2.4 mmol). The reaction mixture was allowed to stir for 18 hours at ambient temperature. The reaction was quenched with water. The aqueous solution was extracted with dichloromethane. The combined dichloromethane was concentrated. The crude product was purified by flash chromatography. Elution with methanol (10%, v/v, in dichloromethane) gave the title compound as red solid: m.p. 156–160° C. 1H NMR (DMSO-d6) δ 11.65 (bs, 1H), 8.32 (s, 1H), 8.19 (d, J=9.0 Hz, 2H), 8.00 (d, J=15.7 Hz, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.62–7.52 (m, 2H), 7.24 (bs, 1H), 6.73 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 1.98–1.94 (m, 1H), 0.88–0.85 (m 4H). MS m/z=454 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]1[C@@H:14]2[C@@:5]([C:15]([OH:17])=[O:16])([C:6]3[C:11]([CH2:12][CH2:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH2:2]1.C(O)(=[O:20])C>O.[O-2].[O-2].[O-2].[Cr+6]>[O:20]=[C:12]1[CH2:13][C@H:14]2[C@:5]([C:15]([OH:17])=[O:16])([CH2:4][CH2:3][CH2:2][CH2:1]2)[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(=O)O
Reactant: O=C(O)[C@]12CCCC[C@H]1CCc1ccccc12
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: O=C1C[C@@H]2CCCC[C@]2(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of the compound from Example 6 (42 g, 0.182 mol) in 900 mL glacial acetic acid was treated dropwise with a solution of chromium trioxide (91 g, 0.912 mol) in 850 mL of glacial acetic acid and 50 mL of water. The reaction was stirred at room temperature for 5 hours and concentrated. The residue was partitioned between benzene and water. The aqueous layer was saturated with NaCl and extracted with additional benzene. The combined organic layers were dried (MgSO4), filtered and concentrated to give a brown solid (37 g). The solid was suspended in 150 mL ethyl acetate and collected by suction filtration, and washed with additional ethyl acetate. The resulting material was dried under vacuum to give the title compound (21.0 g, 47%) as a white solid.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][NH:7][C:8](=[O:19])[CH2:9][CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:10][CH2:9][C:8]([NH:7][CH3:6])=[O:19])=[S:4]
Reactant: NNC(N)=S
Reactant: CNC(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 98.9 %

Procedure:
Thiosemicarbazide (2.60 g, 28.5 mmol) was added to a solution of N-methyl4-oxo-4-phenyl-butyramide (3.33 g, 17.4 mmol), prepared in the previous step, in 60 ml of methanol plus 4.7 ml of 1 N HCl plus 4.7 ml of water and the reaction stirred at room temperature for 22 hours. The reaction was submerged in an ice bath and a solid precipitated. The solid was collected by filtration and dried to give 4.55 g of a white solid. The solid was triturated with water and then dried to give the title compound (4.10 g, 89%) as a white solid, mp 205-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:24]1[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[C:20]1=[O:30]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A reaction vessel was charged with 4.09 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 2.41 of potassium phthalimide and 30 ml of N,N-dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 150 ml of chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and diluted aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, and then concentrated, which afforded 4.67 g of crude 3,5-dichloro-4-(3-phthalimidopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (98% yield).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:16][OH:17]>C1(C)C=CC=CC=1>[OH:17][CH2:16][C@@H:15]1[CH2:18][CH2:19][CH2:20][N:14]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: OC[C@@H]1CCCN1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N2CCC[C@H]2CO)c2ccccc12

Procedure:
1-Cyano-4-fluoronaphthalene (86 mg, 0.5 mmol) was transferred to a Pyrex tube and L-prolinol (197 μL, 2.0 mmol) was added followed by toluene (0.5 mL). The tube was capped and the reaction tube was exposed to microwave irradiation (180° C., 5 min). The reaction mixture was concentrated and purified by flash chromatography on silica gel (eluent: 0-3% methanol in dichloromethane). Yield: 23 mg (18%).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[CH:21]([CH3:23])[CH3:22])[C:3]([CH3:10])=[CH:4][C:5]([O:7]CC)=[O:6].[OH-].[K+]>C(O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[CH:21]([CH3:23])[CH3:22])[C:3]([CH3:10])=[CH:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C=C(C)C(O)c1ccc(OC)c(OC)c1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(O)C(C)=CC(=O)O)c(C(C)C)c1OC
Temperature: 0 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
Compound 8 (9.00 g, 27.9 mmol) was dissolved in 100 mL of ethanol with 3 g of KOH and refluxed for 1 h. The mixture was poured onto 100 g of ice with 25 ml of 6M HCL and stirred for 24 h. The white solid was filtered, washed with water, dried and recrystallized from ether/petroleum ether to give 7.38 g (25.1 mmol, 90%) of 9 as white plates: mp 154°-155° C.; IR 3411 (OH), 1694 (carbonyl), 1644 (alkene) cm-1 ; 1H NMR δ 1.38 (d, J=7.0 Hz, 6 H), 2.00 (s, 3 H), 3.44 (br s, 1 H), 3.85 (s, 6 H), 5.41 (s, 1H), 6.33 (s, 1 H), 6.75 (d, J=8.6 Hz, 1 H), 6.92 (d, J=7.1 Hz, 1 H). Anal. (C6H22 O5) C,H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16]([OH:31])[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:19]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([O:31][C:16]1[CH:15]=[C:14]([Cl:13])[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:17]=1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc(CCOc2cc(O)cc(Cl)c2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(CCOc2cc(Cl)cc(OS(=O)(=O)c3ccc(F)cc3Cl)c2)cc1
Reaction time: 4 h
Yield: 72.1 %

Procedure:
2-Chloro-4-fluorobenzenesulfonyl chloride (1.16 g; 5.0 mmol) was added to a cold solution (ice:water temperature) of 3-chloro-5-[2-(4-cyanophenyl)ethoxy]phenol (0.689 g; 2.5 mmol; from step (ii) above) in pyridine (8 mL). The temperature was allowed to rise (slowly) to ambient overnight. The mixture was re-cooled (ice:water temperature) and ice was added to the reaction flask. After stirring for 4 hours, the pyridine was removed in vacuo. CH2Cl2 was then added and the organic layer was washed with aqueous KHSO4 and water. Drying (MgSO4), evaporation of the solvent and purification by flash chromatography (SiO2; CH2Cl2) afforded 0.84 g (72%) of the sub-title compound.