Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:30][N:27]1[CH2:28][CH2:29][C@@H:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1
Reactant: CN1CC[C@@H](c2nnc3ccc(F)cn23)C1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CC[C@@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate A (203 mg, 1.24 mmol) in dry DMF (3 mL) under N2 was added NaH (60% dispersion in oil, 83.0 mg, 2.07 mmol) (CARE: gas evolution) and the resulting opaque brown solution stirred at RT for 45 min. A solution of Intermediate 90d (228 mg, 1.03 mmol) in dry DMF (2 mL) was added and the dark brown solution stirred at 60° C. under N2 for 90 min. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL) and AcOH (0.1 mL), applied to and SCX-2 cartridge (20 g) and washed with MeOH (75 mL). The product was eluted with 2M NH3 in MeOH (50 mL); concentration in vacuo gave a dark brown solid. FCC, using 5-15% (2M NH3 in MeOH) in DCM, gave the title compound as a light brown powder after freeze-drying (299 mg, 80%). LCMS (Method 3): Rt 0.44 min, m/z 364 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:37]1([C:42](=[S:44])[NH2:43])[CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:44][C:42]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[N:43][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)N1CCCC1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a stirring suspension of N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (1.0 g, 2.36 mmol, 1.0 eq) in DCM (˜5 mL) was added NBS (0.44 g, 2.48 mmol, 1.05 eq). Upon formation of a red solution (˜10 minutes) the reaction mixture was concentrated to a solid and taken up in dioxane (10 mL). To this solution was added MgCO3 (0.38 g) followed by 1-pyrrolidinecarbothioamide (0.384 g, 2.95 mmol, 1.25 eq). After stirring 3 h, the mixture was quenched with water (50 mL) and 1N HCl (10 mL) and stirred 0.25 h. The mixture was filtered and the resultant solid triturated with EtOAc/Hexanes to give 0.52 g (41%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.11 (s, 1H), 8.14 (d, J=5.7 Hz, 1H), 7.65-7.74 (m, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.18-7.29 (m, 5H), 6.44 (d, J=5.5 Hz, 1H), 3.45-3.52 (m, 4H), and 1.98-2.05 (m, 4H).
Reaction SMILES: C[C@H]1CC[C@H]([NH:8][C:9](=[O:27])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15](OCC(OCC)=O)=[C:14]([O:25][CH3:26])[CH:13]=2)CC1.[OH-].[K+]>CO>[CH3:26][O:25][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH:11]=[CH:10][C:9]([NH2:8])=[O:27]
Reactant: CCOC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C=CC(N)=O)c1

Procedure:
Using 28 g of N-(trans-4-methylcyclohexyl )-4-(ethoxycarbonylmethoxy) -3-methoxycinnamamide (Example 171), 100 ml of 254 aqueous potassium hydroxide solution, and 600 ml of methanol, a reaction similar to that conducted in Example 169 was carried out. As a result, 23.9 g of N-(trans-4-methylcyclohexyl )-4-carboxymethoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[C:45]([OH:47])(=[O:46])[CH3:37].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCCC[C@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCCC[C@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Yield: 150.6 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-N6,N6-dimethyl-L-lysine (0.05 g, 0.007 mmole) was dissolved in methanol (1.5 mL). NaBH4 (0.0065 g, 0.0172 mmole) was added and after about 15 min the reaction was complete according to LC-MS. A few drops of acetic acid were added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using 33.5% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.004 g (73%) of the desired product as the acetate-salt was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[C:5]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[N:4][N:3]=1.C(O)(=O)C.CO>C(Cl)Cl.[Pd]>[CH2:22]([N:19]([CH2:20][CH3:21])[CH2:18][CH2:17][CH2:16][NH:15][C:5]1[C:6]2[CH:7]=[C:8]3[N:13]([C:14]=2[C:2]([CH3:1])=[N:3][N:4]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH3:23]
Reactant: CCN(CC)CCCNc1nnc(C)c2c1cc1ccccn12
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)CCCNc1nnc(C)c2c1cc1n2CCCC1

Procedure:
4-(Methyl)-N,N-diethyl-N'-[pyridazino[4,5-b]indolizin-1-yl]-1,3-propanediamine (2.75 g, 8.83 mmoL) was hydrogenated in a Parr appartus with 10% Pd on charcoal (0.54 g) in a 1:1 mixture of acetic acid and methanol at 55 psi and room temperature. Filtration through Solka Floc to remove the catalyst and evaporation of the filtrate gave a crude product which was passed through a pad of alumina eluting with 5% methanol in methylene chloride to give the free base of the title product in quantitative yield. The free base was converted to the monofumarate salt: m.p.171°-172° C.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[N:4]=[C:3]1[NH2:10].[OH:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([C:22](O)=[O:23])([CH2:15]3)[CH2:13]1)[CH2:19]2.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[S:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[N:4]=[C:3]1[NH:10][C:22]([C:14]12[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][C:12]([OH:11])([CH2:21]3)[CH2:13]1)[CH2:20]2)=[O:23]
Reactant: Nc1nc2c(s1)CCC2
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc2c(s1)CCC2)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
A mixture of Example 209A (921 mg, 5.19 mmol), 3-hydroxy-adamantane-1-carboxylic acid (1.22 g, 6.2 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.0 g, 10.4 mmol), 1-hydroxybenzotriazole hydrate (846 mg, 10.4 mmol) and 4-dimethylaminopyridine (196 mg, 1.04 mmol) in pyridine (20 mL) was stirred at room temperature for 12 hours. The solvent was removed and the residue was diluted with water and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, 50% ethyl acetate/hexanes) afforded the title compound. MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:29])=[O:28]
Reactant: CCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 10 h

Procedure:
To a stirred and a cooled solution of lauryl alcohol (186.0 g, 1.0 mole) and triethyl amine (121.0 g, 1.2 mole) in dichloromethane (600 ml), p-toluene sulphonyl chloride (228.0 g, 1.2 mole) in dichloromethane (400 ml) was slowly added and the reaction was continued at room temperature for 10 hours. The reaction mixture was then washed with 20% sodium chloride solution (500 ml). The washed organic layer was dried over anhydrous sodium sulphate. Removal of solvent under vacuo resulted in colorless oil that solidified on keeping to yield lauryl tosylate. (309.0 g, 91%), m. p. 29° C. (literature m. p. 29° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH2:13])[CH:12]=1.N1C=CC=CC=1.[CH2:20]([S:29](Cl)(=[O:31])=[O:30])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][S:29]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])(=[O:31])=[O:30])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: O=C(CS(=O)(=O)Cl)c1ccccc1
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)CC(=O)c2ccccc2)c2c(c1)OC(C)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.2 %

Procedure:
To a solution of 15.5 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine and 10.5 grams of anhydrous pyridine in 100 cc of methylene chloride cooled to 0°-5° C., a solution of 24.5 grams of phenacylsulfonyl chloride in 80 cc of methylene chloride is added. When the dripping is terminated the reaction mixture is warmed to room temperature and stirred for 5 hours. At the end of this time the solution is washed with water, dried over sodium sulfate and concentrated to dryness. Crystallization of the resulting thick oil from ethyl alcohol-ethyl ether gives 16 grams of the compound of the title which melts at 143°-145° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([CH2:24][N:25]([O:29]C(=O)C)[C:26](=[O:28])[CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[NH4+].[Cl-]>CO>[C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([CH2:24][N:25]([C:26](=[O:28])[CH3:27])[OH:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)ON(C[C@H](Cc1ccc(Oc2ccc(Cl)cc2)cc1)NC(=O)OC(C)(C)C)C(C)=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)N(O)C[C@H](Cc1ccc(Oc2ccc(Cl)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a solution of {(S)-1-[(Acetoxy-acetyl-amino)-methyl]-2-[4-(4-chloro-phenoxy)-phenyl]-ethyl}-carbamic acid tert butyl ester (27 mg, 0.057 mmol, 1 eq.) in MeOH (2 ml) was added sodium methoxide (15 mg, 0.27 mmol, 4.7 eq.) until pH=10. The mixture was stirred at room temperature for 30 min. Then was poured into saturated NH4Cl solution (15 ml). The mixture was extracted with dichloromethane (3×5 ml). The combined DCM layers were washed with sodium bicarbonate solution (5 ml) and dried over anhydrous MgSO4. Removal of solvent under reduced pressure gave the desired product (20 mg, 81% yield) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:17][CH2:18][O:19][CH3:20])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@:12]([CH2:17][CH2:18][O:19][CH3:20])([C:14]([OH:16])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: COCC[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of (1S,4S)-4-[(tert-butoxycarbonyl)amino]-1-(2-methoxyethyl)cyclopent-2-ene-1-carboxylic acid (1.56 g, 5.47 mmol) in methanol (30 mL) was added 10% palladium on carbon (150 mg). The mixture was shaken under hydrogen at 50 psi overnight and filtered through celite. The filtrate was evaporated in vacuo to afford the desired product (1.57 g, 99.9%). MS calculated for C14H26NO5 (M+H) 288.2; found 188.2
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:9]1([CH2:15][O:16][C:17]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][OH:23])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1.CO>CN(C)C=O>[C:9]1([CH2:15][O:16][C:17]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][O:23][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])=[O:18])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
[(1,1-Dimethylethyl)dimethylsilyl]chloride (37.5 g., 249 mmol.) was added to a solution of N-[(phenylmethoxy)carbonyl]-L-homoserine [prepared as described in Example 6(a), 41.56 mmol.] in dimethylformamide (125 ml.), followed by imidazole (33.95 g., 498 mmol.). The resulting light yellow solution was stirred at room temperature for 22 hours. Methanol (500 ml.) was added, the reaction mixture was stirred for an additional 6 hours, and then the methanol and most of the dimethylformamide were removed in vacuo. The remaining residue was taken up into ethyl acetate (800 ml.), washed with 10% citric acid (2×300 ml.), and the combined aqueous phase was extracted with ethyl acetate (300 ml.). The combined ethyl acetate phase was washed with water and brine, dried (sodium sulfate), concentrated, and the residue was evaporated with hexane to form a white powder. This powder was dried in vacuo to give 12.942 g. of title product.
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([O:12][CH3:13])=[C:5]([O:14][CH3:15])[CH:4]=1.[C:18]([O:21][CH2:22][CH3:23])(=O)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:6]1[C:5]([O:14][CH3:15])=[CH:4][C:3]([C:3]2[CH:4]=[C:5]3[C:6](=[CH:7][CH:8]=2)[CH:23]=[C:22]([O:21][CH3:18])[C:22]([O:21][CH3:18])=[CH:23]3)=[C:8]([N+:9]([O-:11])=[O:10])[CH:7]=1
Reactant: CCOC(C)=O
Reactant: COc1cc([N+](=O)[O-])c([Sn](C)(C)C)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(-c2ccc3cc(OC)c(OC)cc3c2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (80 mg) and cuprous bromide (16 mg) were added to a solution of 6,7-dimethoxy-2-naphthalenetriflate (10, 220 mg, 0.655 mmol) and trimethyl(3,4-dimethoxy-6-nitrophenyl)stannane (16, 220 mg, 0.64 mmol) in THF (25 mL). The mixture was stirred at room temperature for 0.5 h., and then refluxed under nitrogen for 32 hr. After Cooling, THF was rotaevaporated and ethyl acetate (50 ml) was added to the residue the solution was washed with water (30 mL). The organic layer was separated and passed through a celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel using 60:40 hexanes:ethyl acetate to give compound 17; 1H NMR (CDCl3) d 3.95(3H, s), 3.99(6H, s), 4.01(3H, s), 6.86(1H, s), 7.12(1H, s), 7.14(1H, s), 7.23(1H, dd, J=8.4, J=1.8), 7.56(1H, s), 7.61(1H, d, J=1.7), 7.70(1H, d, J=8.4); 13C NMR d 56.4, 56.9, 106.7, 107.0, 108.3, 114.4, 124.9, 125.7, 127.0, 129.0, 129.5, 132.2, 134.6, 141.6, 148.4, 150.4, 152.7.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](Br)[CH:29]=[CH:30][CH:31]=1)=[O:25].C(N(CC)CC)C.[Cl-].[Li+].Cl>CN(C=O)C.CCOCC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][O:23][C:24]([C:26]1[CH:31]=[C:30]([C:3]2[CH:12]=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[C:10]3[N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:5][CH:4]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CN1CCN(c2cccc3ccc([Sn](C)(C)C)cc23)CC1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc3cccc(N4CCN(C)CC4)c3c2)c1

Procedure:
The title product was prepared following the procedure of example 41 from 7-trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-methoxycarbonyl-1-bromobenzene (0.16 g, 0.74 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) in DMF (12.5 mL) with a heating time of 1.5 hours at 120 to 130° C. The product obtained was 0.15 g (63%) in yield as an oil which was converted to a hydrochloride salt with HCl gas in ether. The solid was collected under a nitrogen atmosphere and recrystallized from chloroform/ether for analysis: mp 201°-203° C.; 13C NMR δ 167.05, 147.37, 141.78, 137.80, 134.08, 131.87, 130.89, 129.57, 129.07, 128.63, 128.47, 126.28, 125.76, 125.02, 120.59, 116.85, 54.30, 52.33, 49.75, 43.70.
Reaction SMILES: COC1C=CC2C(=CC=CC=2)C=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22]CC)=[CH:18][CH:17]=1)([OH:15])=[O:14]>>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CCOc1ccc(C(=O)O)cc1
Agent: COc1ccc2ccccc2c1
Product: O=C(O)c1ccc(O)cc1
Yield: 61.2 %

Procedure:
The method described in Example 4 is applied with the alteration that instead of 2-methoxynaphthalene 3.32 g (20 mmol) of 1-carboxy-4-ethoxybenzene is used yielding 1.86 g (61.2%) of 4-hydroxybenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(OCC)(=O)C.Cl>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)O)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(=O)O)cn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
A mixture of 6-aminonicotinic acid 5.00 g (36.5 mmol) and acetic anhydride 3.80mL (40.2 mmol) in pyridine 30 mL was stirred at 140° C. for 24 hours. To the reaction mixture was added ethyl acetate and acidified with diluted HCl solution to pH 2. The organic layer was washed with water and brine, dried over MgSO4, filtrated and the solvent was evaporated. The residue was washed with diisopropyl ether to give the title compound 1.70 g as off-white solid. Yield 26%.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:43]1[CH2:42][CH2:41][N:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])[CH2:45][CH2:44]1)=[O:20]
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 64.7 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (538 mg, 1.19 mmol, 65%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[S:11][CH2:12][CH2:13][CH2:14][Cl:15].O.O.[Sn](Cl)Cl.[OH-].[NH4+:22]>C(O)C.Cl>[Br:1][C:2]1([NH2:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[S:11][CH2:12][CH2:13][CH2:14][Cl:15]
Reactant: O=[N+]([O-])c1cccc(Br)c1SCCCCl
Reactant: [NH4+]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC1(Br)C=CC=CC1SCCCCl
Temperature: 0 °C
Yield: 93.2 %

Procedure:
1-Bromo-2-[(3-chloropropyl)thio]-3-nitrobenzene (6.78 g, 21.9 mmol) was dissolved in ethyl alcohol (125 mL) and cooled in an ice bath to 0° C. Tin (II) chloride dihydrate (7.4 g, 32.8 mmol) was dissolved in concentrated hydrochloric acid (25 mL) and then added to the first solution over 20 minutes. The reaction was then allowed to warm to room temperature and stirred over night. Reaction mixture was cooled to 0° C. in an ice bath and another (1.5 eq, 7.4 g) of tin (II) chloride dihydrate in concentrated hydrochloric acid (25 mL) was added. This was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature and stirred until loss of starting material. Reaction was then basified to pH 12 with ammonium hydroxide and then filtered. The filtrate was then concentrated to a aqueous slurry, the slurry was then diluted with water (100 mL) and extracted with ethyl acetate (3×300 mL). Organic extracts were dried over magnesium sulfate and filtered. The filtrate was concentrated to give 1-bromo-2-[(3-chloropropyl)thio]-benzenamine (5.7 g, 93.2%). 1H NMR (CDCl3, 300 MHz): δ7.02-60.87 (m, 2H), 6.65 (dd, 1H, J=7.7, 1.9 Hz), 4.63 (s-broad, 2H), 3.68 (t, 2H, J=6.4 Hz), 2.92 (t, 2H, J=6.95 Hz), 2.04-1.95 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1.O>CN(C=O)C>[CH2:1]([O:8][C:14]1[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][N:17]=[C:12]([Cl:11])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)nc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
Benzyl alcohol (5.57 g) was added to a suspension of sodium hydride (oil, 60%, 2.06 g) in DMF (100 mL) by small portions at 0° C., and the obtained mixture was stirred at 0° C. for 30 min. The reaction mixture was cooled to 0° C., 2,4-dichloro-5-nitropyrimidine (10.0 g) was added thereto, and the obtained mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (670 mg). 1H NMR (300 MHz, DMSO-d6) δ 5.62 (2H, s), 7.24-7.73 (5H, m), 9.28 (1H, s).