Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[N:18]=[N:17][C:16]([C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)=[N:15]2)=[CH:11][CH:10]=1.[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43]Br)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]>O1CCCC1.CN(C)C=O>[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43][O:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:16]4[N:17]=[N:18][N:14]([CH2:13][C:12]5[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:27][CH:26]=5)[N:15]=4)[CH:20]=3)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]
Reactant: COc1ccc(Cn2nnc(-c3cccc(O)c3)n2)cc1
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnn(Cc5ccc(OC)cc5)n4)c3)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (0.60 g, 1.83 mmol), 3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenol (0.38 g, 1.35 mmol) (from Example 26 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70° C. for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.41 g, 1.22 mmol) (from Example 1 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 4-chloro-3-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.17 g, 26%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br[CH2:15][C:16]([C:18]1[CH:22]=[C:21]([CH3:23])[O:20][C:19]=1[CH3:24])=O>>[CH3:24][C:19]1[O:20][C:21]([CH3:23])=[CH:22][C:18]=1[C:16]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:15]=1
Reactant: Cc1cc(C(=O)CBr)c(C)o1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Product: COC(=O)c1ccc(-c2nc(-c3cc(C)oc3C)cs2)cc1
Yield: 36 %

Procedure:
In the same manner as in Example 74, methyl 4-thiocarbamoylbenzoate was reacted with 3-bromoacetyl-2,5-dimethylfuran to obtain methyl 4-[4-(2,5-dimethyl-3-furyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 36%. Pale yellow prisms. Melting point: 103 to 105° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=1[CH3:33]>CCOC(C)=O>[Br:8][CH2:33][C:24]1[CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=[CH:28][C:23]=1[O:22][CH3:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CC(=O)O)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)O)cc1CBr
Temperature: 80 °C
Reaction time: 2 h

Procedure:
NBS (2.72 g) and AIBN (0.136 g) were added in one portion to a solution of 2-(4-methoxy-3-methylphenyl)acetic acid (2.99 g) in EtOAc (50 ml) and stirred at 80° C. for 2 h. Another portion of AIBN (0.136 g) was added and the suspension stirred for a further 2 h. The reaction mixture was diluted with EtOAc, washed with sat. sodium thiosulfate solution, 2M HCl, water, and sat. brine. The organic phase was dried, filtered and evaporated to afford the subtitle compound, 4.10 g.
Reaction SMILES: CI.C(=O)([O-])[O-].[K+].[K+].[CH3:9][C:10]1[C:15]([SH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:17]CCCCC>CN(C=O)C.O>[CH3:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[S:16][CH3:17]
Reactant: CCCCCC
Reactant: Cc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1ccccc1C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Methyl iodide (0.5 mL, 8.1 mmol) and potassium carbonate (1.1 g, 8.1 mmol) were added to a solution of o-thiocresol (1.0 g, 8.1 mmol) in 10 mL of DMF. The reaction was stirred at 50° C. for 4 hours and poured into hexane and water. The organic layer was separated, dried over magnesium sulfate and concentrated to afford 1.1 g of desired material.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:9]12([C:19](Cl)=[O:20])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1.C(OCC)(=O)C>[Br:8][C:5]1[S:4][C:3]([NH:2][C:19]([C:9]23[CH2:18][CH:13]4[CH2:12][CH:11]([CH2:17][CH:15]([CH2:14]4)[CH2:16]2)[CH2:10]3)=[O:20])=[N:7][CH:6]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ncc(Br)s1)C12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A mixture of 2-amino-5-bromothiazole monohydrobromide (3.00 g, 11.5 mmol), 1-adamantanecarbonyl chloride (2.74 g, 13.8 mmol), 4-dimethylaminopyridine (1.10 g, 0.90 mmol) and triethylamine (3.20 mL, 23.0 mmol) in 100 mL of THF was stirred at 80° C. for 48 hours. The mixture was cooled to ambient temperature, diluted with 100 ml, of ethyl acetate and washed with brine. The layers were separated and the aqueous phase was extracted with 2×50 mL ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 20% ethyl acetate: 80% hexane) afforded 2.55 g of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.67-1.72 (m, 6 H) 1.92 (d, J=2.8 Hz, 6 H) 1.97-2.04 (m, 3H) 7.55 (s, 1 H) 11.50 (br m, 1 H); MS (DCI/NH3) m/z 341 (M)+, 343 (M+2)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[N].[N+:13]([O-])([OH:15])=[O:14].C(OCC)(=O)C>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1cccc(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [N]
Solvent: CCOC(C)=O
Product: CC(=O)c1cc([N+](=O)[O-])cc(F)c1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 28 %

Procedure:
Under an inert atmosphere of nitrogen 1-(2,3-difluoro-phenyl)-ethanone (5.0 g (32 mmol) was added dropwise to sulphuric acid (95-97%, 20 ml), cooled to 0° C., at such a rate that the temperature was maintained below 5° C. Thereafter, the reaction mixture was cooled to −15° C. and a solution of nitric acid (3.22 ml, 46.4 mmol) in sulphuric acid (95-97%, 4.6 ml) was added dropwise at −15° C. After stirring at −10° C. for 45 minutes, the mixture was poured on ice. Ethyl acetate was added, then the organic layer separated, washed with water, dried over sodium sulphate, and evaporated at reduced pressure. Purification of the crude light yellow oil (5.64 g) by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 yielded the 1-(2,3-difluoro-5-nitro-phenyl)-ethanone (1.83 g, 28% of theory) as a light yellow oil together with a mixture of 1-(2,3-difluoro-5-nitro-phenyl)-ethanone and 1-(2,3-difluoro-6-nitro-phenyl)-ethanone.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][S:11][C@H:12]1[N:15]([CH:16]([C:30]([CH3:32])=C)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:33])[C@H:13]1[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[O:45]=[O+][O-]>CO.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][S:11][C@H:12]1[N:15]([C:16](=[C:30]([OH:45])[CH3:32])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:33])[C@H:13]1[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Yield: 95 %

Procedure:
A solution of 4-nitrobenzyl 2-[(3R,4R)-4[(benzothiazol-2-yl)dithio]-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methyl-3-butenoate (XIIIc. 1.52 g 0.00244 mole) in 2:1 methanol/dichloromethane (165 mL), at -78° C., was treated with a stream of dry ozone until a pale blue coloration was reached (10 min). Nitrogen was then bubbled through the solution to discharge the blue color and methyl sulfide (1.5 mL) was added. The solution allowed to reach 0° C. over the course of 2 h. Evaporation of the solvents gave a crude product which was purified by flash-chromatography over silica gel (65% ethyl acetate in hexane) to yield 1.448 g (95%) of the title compound, XIVb, as a white foam.
Reaction SMILES: [CH2:1]1[CH2:6][CH:5]([C:7]2([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26](NC4NN=NN=4)[CH:25]=3)=[O:22])[N:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([CH3:18])[C:8]2=[O:19])[CH2:4][CH2:3][CH2:2]1.[NH:36]1[C:40]([NH:41][CH2:42]C2C=C(C=CC=2)N)=[N:39][N:38]=[N:37]1>C(#N)C>[CH2:3]1[CH2:4][CH:5]([C@@:7]2([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:42][NH:41][C:40]4[NH:39][N:38]=[N:37][N:36]=4)[CH:25]=3)=[O:22])[N:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([CH3:18])[C:8]2=[O:19])[CH2:6][CH2:1][CH2:2]1
Reactant: Nc1cccc(CNc2nnn[nH]2)c1
Reactant: CN1C(=O)C(NC(=O)Nc2cccc(Nc3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21
Solvent: CC#N
Product: CN1C(=O)[C@@](NC(=O)Nc2cccc(CNc3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21

Procedure:
The title compound was prepared from Intermediate 3 and 3-[(tetrazol-5-yl)aminomethyl]aniline using a similar method to that described for Example 4, except that anhydrous acetonitrile was used instead of tetrahydrofuran; the crude product was purified by flash chromatography (silica gel, dichloromethane-methanol, 95:5 to 90:10) and recrystallized from a mixture of methanol and ethyl acetate; mp 175°-178° C.; [α]D24 +17.4° (c=0.50, dimethylformamide); the spectroscopic properties of this material (1 H-NMR and MS spectra) were identical to those described for its racemate (Example 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[S:10]([NH:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: NS(=O)(=O)c1ccc(F)cc1NS(=O)(=O)/C=C/c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(F)cc1NS(=O)(=O)CCc1ccc(Cl)cc1
Yield: 49.3 %

Procedure:
2-[[(E)-2-(4-Chlorophenyl)ethenyl]sulfonylamino]-4-fluoro-benzenesulfonamide (120 mg, 0.31 mmol) was dissolved in ethyl acetate (5 ml) and subjected to the H-cube (1 ml/min, full hydrogen. 10% Pd/C). The product obtained was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (60 mg, 49%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[N:17]=[C:16]([O:18]CC2C=CC=CC=2)[C:15]([F:26])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])C1C=CC=CC=1>O1CCOCC1.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[N:17]=[C:16]([OH:18])[C:15]([F:26])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1cc(F)c(OCc2ccccc2)nc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(F)c(O)nc1O
Yield: 105.3 %

Procedure:
Next, 2,6-dibenzyloxy-5-fluoronicotinic acid (5.00 g) was dissolved in dioxane (50 mL), and 20% palladium hydroxide (50% wet, 500 mg) was added thereto and reacted under a hydrogen atmosphere for 1 hour. The palladium hydroxide was filtered through Celite from the resulting reaction product, and the solvent was evaporated to obtain a compound, i.e., 2,6-dihydroxy-5-fluoronicotinic acid (2.58 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[NH:12][C:13]([CH2:15]O)=[N:14][C:10]=2[CH:9]=1)([O-:7])=[O:6]>C(Cl)Cl>[Cl:3][CH2:15][C:13]1[NH:12][C:11]2[CH:17]=[CH:18][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][C:10]=2[N:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]c(CO)nc2c1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2[nH]c(CCl)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 mL (275 mmol) thionyl chloride are added slowly to a solution of 6.4 g (33.1 mmol) (5-nitro-1H-benzimidazol-2-yl)-methanol in 100 mL DCM at 10° C. The reaction is stirred for 1 h at RT and the solvent is eliminated i.vac. The residue is triturated with DCM, suction filtered, washed with DCM and ether and dried in the circulating air dryer at 35° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][C:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([CH3:15])[CH3:14].[OH-].[Na+]>CO>[CH3:15][C:13]([C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)=[O:3])=[CH:22][CH:23]=1)([CH3:12])[CH3:14]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2ccc(C(C)(C)C)cc2)cc1
Temperature: 30 °C
Yield: 89.9 %

Procedure:
97.6 g (0.65 mol) of 4-methoxyacetophenone and 105.4 g (0.65 mol) of 4-(1,1-dimethylethyl)benzaldehyde were dissolved in 600 ml of methanol in a 1 1 round-bottom flask fitted with internal thermometer, reflux condenser and paddle stirrer. 20 g (0.05 mol) of 10% NaOH were then added at room temperature. The mixture was then stirred at 30° C. The crystals which formed were filtered off, washed with 50 ml of cold methanol and then dried under reduced pressure (150 mbar) at 75° C. Yield: 172 g (90% yield) of pale yellow crystals; m.p.: 114-116° C.; purity: >99%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[S:25][CH:26]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[S:25][C:26]=2[Br:1])[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCN(c2csc3cc(F)ccc23)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2c(Br)sc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
In an alternative procedure, add N-bromosuccinimide (1.319 g, 6.62 mmol) to a stirring solution of 4-(6-fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 46a) (2.226 g, 6.62 mmol) in CCl4 and reflux for 2 h. Allow cooling to room temperature and filter. Evaporate the solvent and purify the residue by chromatography over silica gel (EtOAc/heptane, 9:1) to obtain 2.34 g (94%) of oil.
Reaction SMILES: CN(C)C=O.S(Cl)(Cl)=O.C[N+](C)=C[Cl:13].[Cl-].O[CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])[C:18]([OH:20])=[O:19]>ClCCl>[Cl:13][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])[C:18]([OH:20])=[O:19]
Reactant: C[N+](C)=CCl
Reactant: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(O)C(Cl)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a magnetically stirred N,N-dimethylformamide (20 ml, 258.5 mmol) cooled in ice was added slowly dropwise thionyl chloride (30 ml, 411.2 mmol). To the resulting cold Vilsmeier reagent was added dichloromethane (100 ml), α-hydroxy-2-nitrobenzenepropanoic acid (20.0 g, 94.7 mmol) and a further 50 mL of dichloromethane as a rinse. The mixture, protected from extraneous moisture, was stirred at room temperature until solution was achieved and the solution was left at room temperature (25° C.) overnight. The solution was poured onto stirred ice and the mixture stirred for 1 hour during which time it warmed to room temperature. The dichloromethane layer was separated, washed thrice with water, dried (MgSO4) and evaporated to a syrup. The syrup was concentrated further at 40° C. under oil pump vacuum to remove traces of N,N-dimethylformamide. The resulting syrup was stirred magnetically with water while cooling in ice. The resulting solid was ground in a mortar and collected on a filter. The solid was then stirred magnetically with water, collected on a filter and washed with water. Drying under vacuum over phosphorus pentoxide at room temperature provided 19.60 g (90%) of titled product, mp 107°-109° C.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Br[CH:24]([CH:27]=O)[CH:25]=[O:26].CN(C)C(=O)C>O>[OH:26][CH2:25][C:24]1[S:14][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])=[N:13][CH:27]=1
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=CC(Br)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 80 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (1.00 g), bromomalonaldehyde (0.86 g) and N,N-dimethylacetamide (8 ml) was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. The obtained crystals were dissolved in tetrahydrofuran (8 ml) and methanol (8 ml), sodium borohydride (63 mg) was added at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were collected by filtration, washed with water, and dried. The crystals were subjected to silica gel column chromatography to give the title compound (0.43 g, yield 39%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). melting point 201-202° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[CH2:14]([C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH:24]2[C:29](=O)[CH2:28][CH2:27][N:26]([CH3:31])[CH2:25]2)=[CH:18][C:17]=1[O:32][CH3:33])[CH3:15]>O1CCCC1>[CH2:14]([C:16]1[C:17]([O:32][CH3:33])=[CH:18][C:19]([CH:24]2[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28]/[C:29]/2=[CH:5]\[C:3]([O:2][CH3:1])=[O:4])=[CH:20][C:21]=1[O:22][CH3:23])[CH3:15]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CCc1c(OC)cc(C2CN(C)CCC2=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1c(OC)cc(C2CN(C)CC/C2=C\C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A solution of 39 ml (262.4 mmol) of trimethyl phosphonoacetate in 450 ml of tetrahydrofuran was added dropwise at 0° to a suspension of 9.54 g (238.5 mmol) of sodium hydride (55% in mineral oil) in 450 ml of tetrahydrofuran and the mixture was stirred for 30 minutes. Subsequently, the white suspension was treated with a solution of 33.15 g (119.5 mmol) of 3-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-piperidin-4-one in 450 ml of tetrahydrofuran and the mixture was stirred at 50° for 2 hours. After cooling to room temperature the mixture was poured on to 500 ml of ice-water and extracted three times with 400 ml of diethyl ether. The organic phases were washed with 400 ml of water and 400 ml of saturated sodium chloride solution, dried (Na2SO4), filtered and evaporated. Chromatography (silica gel, methylene chloride/methanol 19:1) and recrystalization from hexane yielded 36.33 g (91%) of methyl (E)-[3-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-piperidin-4-ylidene]acetate as pale yellow crystals of m.p. 110-112°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1.O>[CH3:29][S:30]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a mixture of 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (500 mg, 1.68 mmol) and triethylamine (340 mg, 3.36 mmol) in tetrahydrofuran was added methanesulfonyl chloride (385 mg, 3.36 mmol) by portion and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate and evaporated under reduced pressure to a residue, which was chromatographed and then recrystallized to afford 2-methanesulfonylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (447 mg, 71% yield): mp 127.5°-129.0° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[C:4]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccnc1Oc1cccc(C=C2CCNCC2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccnc1Oc1cccc(C=C2CCN(C(=O)Nc3cccnc3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
3-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Step 5), phenyl pyridin-3-ylcarbamate (333 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):CH2Cl2) to afford the title compound (445 mg) as a foamy white solid. MS (APCI 10V) AP+ 401.4, 281.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.33 (s, 3H) 2.44 (td, J=5.81, 1.29 Hz, 2H) 2.57 (td, J=5.92, 1.22 Hz, 2H) 3.50-3.57 (m, 2H) 3.61-3.68 (m, 2H) 6.44 (s, 1H) 6.83-6.94 (m, 2H) 7.00-7.09 (m, 2H) 7.28-7.41 (m, 2H) 7.64-7.74 (m, J=7.28, 2.03, 1.07, 1.07 Hz, 1H) 7.87-7.96 (m, 2H) 8.16 (dd, J=4.80, 1.44 Hz, 1H) 8.58 (dd, J=2.60, 0.72 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([CH2:22][O:23][CH3:24])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.Cl.C([N:28]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([CH2:22][O:23][CH3:24])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:28])=[O:13])=[CH:8]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COCc1ccc(Oc2cc(OC)c3[nH]c(C(=O)O)cc3c2)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCc1ccc(Oc2cc(OC)c3[nH]c(C(N)=O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
A mixture of 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (2.28 g), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.66 g), 1-hydroxybenzotriazole (2.13 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 20 min. A solution of 25% ammonium hydroxide (3 mL) was added to the mixture. After stirring at room temperature for 15.5 h, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was solidified with ethyl acetate-diethyl ether and the resulting solid was washed with diethyl ether to give the title compound (1.65 g, 73%) as a pale orange solid. MS 328 (MH+).