Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.CSC.[CH:5]1([C:15](C)(C)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1.[ClH:35].O.CO>C1COCC1>[OH2:6].[ClH:35].[ClH:35].[CH2:31]([O:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([CH2:16][CH2:15][CH:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][CH2:7][O:6]3)[CH2:19][CH2:20]2)=[CH:29][CH:28]=1)[CH3:32]
Reactant: CCOc1ccc(N2CCN(C(=O)C(C)(C)C3OCCc4ccccc43)CC2)cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(N2CCN(CCC3OCCc4ccccc43)CC2)cc1

Procedure:
Borane-methyl sulfide (0.8 ml, 0.08 mol) is added to a mixture of 2-(isochroman-1-yl)-1-[4-(4-ethoxyphenyl)piperazin-1-yl]-2-methylpropan-1-one (LXXXII, 0.279 g, 0.73 mmol) in THF (5 ml). The mixture is heated at 76° for 3 hr, then cooled in an ice/water bath. Hydrochloric acid/water (10%, 0.95 ml) is added, followed by methanol. The mixture is concentrated and additional methanol is added and removed under reduced pressure. This is repeated two more times. The residue is partitioned between dichloromethane and aqueous saturated sodium bicarbonate and the combined organic phases are separated and dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel eluting with methanol/dichloromethane (2/98). The appropriate fractions are pooled and concentrated to give the free base of the title compound. The dihydrochloride salt is prepared by dissolving the material in methanol and adding methanol saturated with hydrochloric acid to give the title compound, mp 211-212°; MS (m/z) 366; IR (mineral oil) 1510, 1117, 2329, 1257, 1475 and 2259 cm-1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C=O)=[N:4][C:3]=1[CH2:10][C:11]([NH:13][C@@H:14]1[C:30](=[O:31])[N:16]2[C:17]([C:27]([OH:29])=[S:28])=[C:18]([C:21]3[S:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH2:19][S:20][C@H:15]12)=[O:12].CO.Cl.[OH-].[Na+]>C(OCC)(=O)C.O1CCCC1>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3]([CH2:10][C:11]([NH:13][C@@H:14]2[C:30](=[O:31])[N:16]3[C:17]([C:27]([OH:29])=[S:28])=[C:18]([C:21]4[S:22][C:23]([CH3:26])=[N:24][N:25]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:4]=1
Reactant: Cc1nnc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4nc(NC=O)sc4Cl)[C@H]3SC2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nnc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4nc(N)sc4Cl)[C@H]3SC2)s1
Temperature: 35 °C
Reaction time: 5 h
Yield: 52.3 %

Procedure:
To a suspension of 7β-[2-(5-chloro-2-formylaminothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (380 mg), methanol (4 ml) and tetrahydrofuran (4 ml) was conc-hydrochloric acid (153 μl). The mixture was stirred for 5 hours at 35° C. The reaction mixture was added to a mixture of ethyl acetate (20 ml) and ice-water (50 ml). To the aqueous solution was added ethyl acetate (20 ml). The mixture was adjusted to pH 7 with 1N-sodium hydroxide solution. To the separated aqueous solution was added ethyl acetate (20 ml). The mixture was adjusted to pH 2 with 1N-hydrochloric acid. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give 7β-[2-(2-amino-5-chlorothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (188 mg).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].C(C(C([O-])=O)C([O-])=O)C.[K+].[K+].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31](C(O)=O)[C:32]2[NH:36][C:35]([CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:34][C:33]=2[CH:45]=1.[Mg+2].[C:50]([O:56][CH2:57][CH3:58])(=[O:55])[CH2:51][C:52]([O-])=[O:53].C(OC(=O)CC([O-])=O)C.Cl.C(=O)(O)[O-].[Na+]>O.O1CCCC1.C(#N)C.C(N(CC)CC)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:52](=[O:53])[CH2:51][C:50]([O:56][CH2:57][CH3:58])=[O:55])[C:32]2[NH:36][C:35]([CH2:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[N:34][C:33]=2[CH:45]=1
Reactant: COc1cc(C(=O)O)c2[nH]c(CCc3ccccc3)nc2c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CCC(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(OC)cc2nc(CCc3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (1.3 mL) and magnesium chloride (1.06 g) were added to anhydrous acetonitrile (15 mL) suspension of potassium ethylmalonate (1.58 g), and the mixture was vigorously stirred at room temperature for 18 hours under an atmosphere of argon. Next, a catalytically effective amount of N,N-dimethylaminopyridine and N,N-carbonyldiimidazole (663 mg) were added to anhydrous tetrahydrofuran (12 mL) suspension of 6-methoxy-2-(2-phenylethyl)benzimidazole-4-carboxylic acid (1.1 g) obtained in Reference Example 21, and the mixture was stirred for 2 hours under an atmosphere of argon. The reaction solution was added to the previously prepared suspension of ethyl malonate magnesium salt while cooling in an ice bath, and the mixture was stirred at room temperature for 2 hours. While cooling in an ice bath, this was diluted with water and adjusted to pH 1 with 4 N hydrochloric acid. At the same temperature, this was adjusted to pH 7 to 8 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) and the desired fraction was concentrated to obtain the title compound as crystal (620 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][CH2:15][CH2:14][C@H:13]1[CH2:12][O:11][NH:10]2>[Zn].C(O)(=O)C>[NH2:10][C@:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C@H:13]([CH2:12][OH:11])[CH2:14][CH2:15][O:16][CH2:17]1
Reactant: Fc1ccc([C@]23COCC[C@H]2CON3)c(F)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2ccc(F)cc2F)COCC[C@H]1CO
Reaction time: 18 h

Procedure:
(3aR,7aS)-7a-(2,4-Difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C10) (1.06 g, 4.39 mmol) was mixed with acetic acid (10 mL); after addition of zinc powder (3.74 g, 57.2 mmol), the reaction mixture was stirred for 18 hours. Insoluble material was removed via filtration, and the filtrate was concentrated under reduced pressure. The resulting paste was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. Filtration and removal of solvent under reduced pressure provided the product. Yield: 900 mg, 3.70 mmol, 84%. 1H NMR (400 MHz, CD3OD) δ 1.71-1.78 (m, 1H), 2.00-2.12 (m, 1H), 2.40-2.48 (m, 1H), 3.37-3.40 (m, 2H), 3.50 (d, J=11.5 Hz, 1H), 3.62 (ddd, J=12.7, 11.5, 2.7 Hz, 1H), 4.01 (dd, J=11.3, 2.0 Hz, 1H), 4.09-4.15 (m, 1H), 6.96-7.05 (m, 2H), 7.64-7.71 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(C)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1. the desired compound was prepared from 12 g of ethyl 2-aminothiazol-4-ylglyoxylate. 10 g of p-tolyl isocyanate and 80 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: O.O.Cl.Cl.[N:5]1([C:11]2[S:12][N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:34](=[O:35])[CH2:33][C:28]2([CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:27][C:26]1=[O:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[N:13]1[S:12][C:11]([N:5]2[CH2:10][CH2:9][N:8]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[C:26](=[O:36])[CH2:27][C:28]4([CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:33][C:34]3=[O:35])[CH2:7][CH2:6]2)=[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=12
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)snc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2snc3ccccc23)CC1

Procedure:
Title product dihydrochloride dihydrate--A mixture of 3-(1-piperazinyl)-2,1-benzisothiazole (4.0 g., 0.018 mole) and 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione (5.5 g., 0.018 mole), anhydrous potassium carbonate (4.98 g., 0.036 mole) and potassium iodide (0.83 g., 0.005 mole) in 100 ml. of acetonitrile is stirred at reflux temperature for a period of 20 hr. The reaction mixture is filtered, concentrated in vacuo and residual material triturated with ether to afford 7.38 g., (93% yield) of the title product free base. Conversion of the free base to the hydrochloride salt in ethanol with ethanolic hydrogen chloride and crystallization from ethanol affords 5.34 g. (57% yield) of analytically pure 8-[4-[4-(2,1-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride hemihydrate, m.p. 225°-227° C. (dec.).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=[O:2].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:11][C:12]([F:14])([F:13])[CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[OH:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1cccc(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)C(F)(F)F)c1
Yield: 92 %

Procedure:
According to Reference Example 8-12, by use of 3-formylbenzonitrile (500 mg, 3.81 mmol), (trifluoromethyl)trimethylsilane (678 μL, 4.58 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 381 μL, 0.381 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 3 hours. Then, purification by silica gel column chromatography (hexane/ethyl acetate=7/3) was performed to give 3-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile (Compound CZ) (705 mg, yield: 92%).
Reaction SMILES: [CH:1]([S:4]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: CC(C)S(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)C(C)C)n1

Procedure:
A mixture of 7.0 g. 3-isopropylsulphonyl-1,2,4-triazole, 7.0 ml. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed for 1 hour under anhydrous conditions. The reaction mixture was worked up as described in Example 1 to give 1-diallylcarbamoyl-3-isopropylsulphonyl-1,2,4-triazole as an oil which was heated under reduced pressure (100° C./0.5 mm.) for 1 hour to remove all traces of volatile material. Refractive index of product nD26 1.5158. Elemental analysis satisfactory.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]#[C:8][C:9]1[C:10]([CH:23]=[O:24])=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1.[H][H]>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][C:9]1[C:10]([CH:23]=[O:24])=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:19])([CH3:20])[C:17]=2[CH:18]=1
Reactant: [H][H]
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(C#Cc3ncccn3)cc21
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(CCc3ncccn3)c(C=O)cc21
Yield: 68.3 %

Procedure:
To a solution of 0.362 g (1.14 mmol) of 3-(2-(2-pyrimidyl)ethynyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde in 20 mL of ethanol was added 0.060 g of 10% palladium on carbon and the suspension was shaken under 40 psi hydrogen gas for 3 hours. The resulting solution was filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford 0.251 g (68%) of 3-(2-(2-pyrimidyl)ethyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p.=78.0-84.5° C.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([O:14][CH3:15])=[N:12][N:11]([CH3:16])[C:10]1=[O:17].[Cl:18][C:19]1[CH:29]=[CH:28][C:22]([NH:23][C:24](=[S:27])[CH2:25][CH3:26])=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[CH3:15][O:14][C:13]1[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][S:27][C:24](=[N:23][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:29][CH:28]=2)[CH2:25][CH3:26])[C:10](=[O:17])[N:11]([CH3:16])[N:12]=1
Reactant: COc1nn(C)c(=O)n1-c1ccccc1CBr
Reactant: CCC(=S)Nc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=Nc1ccc(Cl)cc1)SCc1ccccc1-n1c(OC)nn(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a solution of 0.50 g of the title compound of Step D in 2 mL of THF was added 0.37 g of 4'-chlorothiopropionanilide and then 0.23 g of potassium tert-butoxide. (An exotherm occurred during this addition). The reaction was allowed to stir at room temperature overnight and then was heated briefly to reflux and allowed to cool. The reaction mixture was diluted with ethyl acetate and washed successively with water and then with saturated aqueous NaCl. The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (50-60% ethyl acetate/hexanes) to afford 0.48 g of the title compound of Step E (about 95% pure), a compound of the invention. 1H NMR (CDCl3): δ 7.58 (m,1H), 7.37 (m,2H), 7.23 (m,3H), 6.60 (d,2H), 4.23 (s,2H), 3.86 (s,3H), 3.41 (s,3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:15]([C:16]([OH:19])([CH3:18])[CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10](Cl)=[N:11][C:12]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)C.[NH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[C:30]=2[CH:29]=[CH:28]1>>[OH:4][CH2:5][CH2:6][N:7]1[C:15]([C:16]([OH:19])([CH3:18])[CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]3[C:30]=1[CH:29]=[CH:28][NH:27]3)=[N:11][C:12]=2[N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: CC(=O)OCCn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: OB(O)c1cccc2[nH]ccc12
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(-c3cccc4[nH]ccc34)nc2n1CCO

Procedure:
2-(2-Chloro-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purin-9-yl)ethyl acetate (165 mg) was treated with indole-4-boronic acid via General Procedure A and purified via reverse phase HPLC to give 21 mg of 101 as a white solid. MS (Q1) 423.2 (M)+
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][CH2:11][C@H:12]([CH3:39])[O:13][C:14]1[CH:15]=[C:16]([CH:27]=[C:28]([C:30]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH3:38])[N:34]=2)=[O:31])[CH:29]=1)[O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1.CN(C(ON1N=N[C:50]2[CH:51]=[CH:52][CH:53]=[N:54][C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C>[OH:10][CH2:11][C@H:12]([CH3:39])[O:13][C:14]1[CH:29]=[C:28]([CH:27]=[C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:54]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]3)=[O:24])=[CH:20][CH:19]=2)[CH:15]=1)[C:30]([NH:32][C:33]1[CH:37]=[CH:36][N:35]([CH3:38])[N:34]=1)=[O:31]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCCCC3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
DIPEA (0.36 mL, 1.95 mmol) was added to a suspension of 4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)benzoic acid (200 mg, 0.49 mmol), HATU (390 mg, 1.02 mmol) and piperidine (0.19 mL, 1.95 mmol) in DMF (3 mL) and the mixture stirred at, ambient temperature for 24 hours. The solvent was evaporated. Water (30 mL) was added and the mixture extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried, (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-20% methanol in ethyl acetate, to give the desired compound (167 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[O:7])=[CH:34][CH:35]=1)(=[O:38])[CH3:37]
Reactant: Cc1cc(C)cc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cc(C)cc(C)c2)cc1
Yield: 86.4 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3,5-dimethylphenyl)benzamide (382.8 mg, 0.81 mmol) and acetic anhydride (0.092 ml, 0.99 mmol), the procedure of Inventive Example 94 was repeated to obtain 360.9 mg (86.4%) of the title compound in a light brown amorphous form.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][C:11]1[CH:12]=[C:13]([C:18](Cl)=[O:19])[C:14]([Cl:17])=[N:15][CH:16]=1>C(OCC)C>[Br:10][C:11]1[CH:12]=[C:13]([C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=2[Cl:1])=[O:19])[C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Reactant: Nc1cccc(Cl)c1Cl
Solvent: CCOCC
Product: O=C(Nc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 2,3 dichloroaniline (3.875 g, 23.914 mmol) in diethyl ether (20 mL) was added 5-bromo-2-chloropyridine-3-carbonyl chloride (3.0 g, 11.96 mmol). The reaction was stirred overnight. The precipitated solids were collected and washed with diethyl ether to provide 3.6 g of 5-bromo-2-chloro-N-(2,3-dichlorophenyl)pyridine-3-carboxamide as a cream colored solid [LC-MS m/e=380.0 (M+H)]. Using the same procedure, 5-bromo-2-chloro-N-(2,3-fluorophenyl)pyridine-3-carboxamide and 5-bromo-2-chloro-N-(3-chloro-2-fluorophenyl)pyridine-3-carboxamide can be produced from reacting 5-bromo-2-chloropyridine-3-carbonyl chloride with 2,3 fluoroaniline and 3-chloro-2-fluoroaniline, respectively.
Reaction SMILES: CN=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([N+]([O-])=O)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:28]=[C:29]([SH:34])[CH:30]=[CH:31][C:32]=1[Cl:33].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([S:34][C:9]2[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:4]3[C:3]([O:7][C:6](=[O:8])[C:5]=23)=[O:19])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: O=C1OC(=O)c2c(Sc3ccc(Cl)c(Cl)c3)cc([N+](=O)[O-])cc21
Reaction time: 8 h

Procedure:
18.84 g (75 mmols) of 3,5-dinitrophthalic acid N-methylimide [prepared according to Example 2] are initially introduced into 250 ml of ethyl acetate and treated with 30.4 g (220 mmols) of ground, anhydrous potassium carbonate, and 14 g (78 mmols) of 3,4-dichlorothiophenol are then added dropwise. After the addition of 95 ml of tetrahydrofuran, the mixture is stirred overnight and then evaporated to dryness. The residue is kept under reflux overnight in 100 ml of water, the mixture is extracted at 25° C. with petroleum ether and filtered and the aqueous filtrate is acidified with 300 ml of 2 N HCl and heated under reflux. After 2.5 hours, the mixture is cooled and extracted with tetrahydrofuran/toluene and the extract is washed with saturated NaCl solution, dried over sodium sulfate and evaporated. The residue is warmed to the reflux temperature with 100 ml of toluene and 7.66 g (75 mmols) of acetic anhydride and, after cooling, the mixture is evaporated. After recrystallisation from methylene chloride/n-pentane, 22.2 g (80% of theory) of 3-(3,4-dichlorophenylthio)-5-nitrophthalic anhydride are obtained; melting point: 154°-7° C.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[CH:12]=[N:11][C:10]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[N:18][C:9]2=3)[CH2:4][O:3]1.Cl>O1CCCC1>[OH:3][CH2:4][CH:5]([N:8]1[C:13](=[O:14])[CH:12]=[N:11][C:10]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[N:18][C:9]1=2)[CH2:6][OH:7]
Reactant: COc1ccc2ncc(=O)n(C3COC(C)(C)OC3)c2n1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2ncc(=O)n(C(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
4-(2,2-Dimethyl-1,3-dioxan-5-yl)-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (17.40 g, 59.7 mmol) was dissolved in tetrahydrofuran (THF) (220 ml) to give a dark yellow solution. 1M HCl aq. (200 ml) was added (transient blue and green colours appeared in the solution) and the now light yellow solution was stirred at room temperature for 1 hour. The mixture was concentrated to ca.300 ml on a rotary evaporator using a cold water bath (some solid was precipitated during this procedure) then was stirred vigorously while solid sodium hydrogen carbonate was added in portions (caution: effervescence) until the mixture was ca. pH 8. The resulting yellow solid was collected by filtration with suction, washed with water (2×20 ml) and air-dried to give the title compound as an amorphous yellow solid (13.805 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=O)[CH:6](Br)[CH2:7][CH2:8][CH3:9].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[S:20])=[CH:17][CH:16]=1>C(O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[N:21]=[C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:23][CH:22]=2)[S:20][C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(Br)C(=O)CC(=O)OC
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CC(=O)OC
Temperature: 25 °C
Yield: 99.2 %

Procedure:
4-Bromo-3-oxo-heptanoic acid methyl ester (6.0 g, 25.0 mmol) is dissolved into denatured ethanol (100 mL) and para-trifluoromethyl thiobenzamide (5.0 g, 24.4 mmol) is added in one portion. The reaction is purged of air and flushed with nitrogen then heated to reflux. The reaction is monitored by TLC and HPLC and when complete, the reaction is allowed to cool to room temperature. The solvent is removed and the reaction is diluted with ethyl acetate (200 mL), followed by ishes with saturated sodium bicarbonate solution, water, and brine. The ethyl acetate solution is dried over anhydrous sodium sulfate, then concentrated add further purified using flash column chromatography (10% EtOAc/Hexanes) to yield pure [[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester (8.66 g, 24.2 mmol) or 98% yield.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[C:6]1=O)C.[N+]([O-])(O)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]([NH2:35])=[NH:34])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]2[N:35]=[CH:4][C:5]3[CH2:11][C:10](=[O:12])[NH:9][C:8]4[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=4[C:6]=3[N:34]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(NC(=N)N)cc1OC
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Solvent: O=[N+]([O-])O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for method I, 4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-c) and N-(3,4-dimethoxyphenyl)guanidine nitrate were converted to I-27 (58%): HRMS Calcd. for C20H18N4O3: 363.1457, Found 363.1441.