Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[C:29]([Cl:45])=[CH:28][N:27]=1>>[Cl:45][C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39](=[O:41])(=[O:40])[N:42]([CH3:43])[CH3:44])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(N)c2OC
Product: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC
Yield: 33.7 %

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2,2,2-trifluoro-acetamide (164 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (160 mgs) gave the title compound as an off-white solid (102 mgs). 1H-NMR (CDCl3, 400 MHz): 9.47 (s, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.33 (d, J=8.9 Hz, 1H), 8.21 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.67-7.54 (m, 3H), 7.32-7.28 (m, 1H), 6.92 (d, J=8.8 Hz, 1H), 4.47-4.34 (m, 2H), 3.87 (s, 3H), 3.58-3.54 (m, 1H), 3.17-3.13 (m, 1H), 2.78 (s, 6H), 2.59-2.53 (m, 1H), 2.06-2.01 (m, 1H), 1.23-1.18 (m, 3H); LC/MS: found (M+H)+=656; MP: 250-51° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[Cl:9].C1COCC1.C([Mg]Cl)(C)C.[CH:20]1[CH2:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Cl:9][C:3]1[CH:2]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH:24]1[CH2:23][CH:22]2[CH:21]=[CH:20]1
Reactant: Clc1cccc(Br)c1Cl
Reactant: C1=CCC=C1
Agent: CC(C)[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Clc1cccc2c1C1C=CC2C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 117.9 %

Procedure:
115 g of 1-Bromo-2,3-dichlorobenzene was dissolved in 470 g of toluene and the solution was cooled down to −10° C. Then a 20% THF solution of isopropylmagnesium chloride (309 g) was added over 30 min and the reaction mixture was stirred 1 hour at −10° C. Freshly distilled cyclopentadiene (44.5 g, 1.3 eq) was added over 10 min. After one hour stirring at ambient temperature, the mixture was heated to reflux. When the conversion was completed, the reaction mixture was filtered off and washed twice with toluene. The mother liquor was evaporated and 106 g of brown crude oil was obtained (yield: 91.5%. The material can be purified by distillation or by CC (silica gel, eluant: Hept/TBME 19/1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](N(CC)CC)C>S(Cl)(Cl)=O>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(Br)c1C
Temperature: 60 °C
Yield: 70.1 %

Procedure:
A suspension of 3-bromo-2-methylbenzoic acid (9.9 g,46 mmol) in thionyl chloride (20 mL) was heated to 60° C. for 1 hour, cooled to room temperature, and concentrated. The residue was suspended in 50 mL of methanol, cooled to 0° C., treated slowly with triethylamine (12.7 μL, 92 mmol), warmed to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water and the organic phase was washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to give 7.39 g of the desired product. Rf=0.5 (10% ethyl acetate/hexanes).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:16]=1[NH2:17]>ClC1C=CC=CC=1>[NH2:9][C:10]([NH2:11])=[NH:17].[ClH:14].[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([NH:17][C:16]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:15]=2[Cl:14])=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: CCc1cccc(N(C)C#N)c1
Agent: Cl
Solvent: Clc1ccccc1
Product: CCc1cccc(N(C)C(=N)Nc2cc(Cl)ccc2Cl)c1
Product: N=C(N)N

Procedure:
A mixture of N-(3-ethylphenyl)-N-methylcyanamide (520 mg, 3.3 mmol), 2,5-dichloroaniline hydrochloride (600 mg, 3 mmol), and chlorobenzene (2 mL) were combined in a dry round bottom flask equipped with a water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 4 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., 15 hours) to yield the title compound, N-(3-ethylphenyl)-N-methyl-N'-(2,5-dichlorophenyl)guanidine hydrochloride, as a white solid (760 mg, 72% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[C:11]([Cl:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH2:19]C)[C:7]([O:15][CH2:16]C)=[N:8]2.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:13][C:12]1[C:3]([CH2:2][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:14])[N:8]=[C:7]([O:15][CH3:16])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOc1nc2cc(Cl)c(Cl)c(CBr)c2nc1OCC
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1nc2cc(Cl)c(Cl)c(Cn3cncn3)c2nc1OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
A mixture of 5-bromomethyl-6,7-dichloro-2,3-diethoxyquinoxaline (Preparation 1,176 mg, 0.5 mmol), 1,2,4-triazole (69 mg, 1.0 mmol) and anhydrous potassium carbonate (138 mg, 1.0 mmol) in dry N,N-dimethylacetamide (2 mL) was heated at 50° C. with stirring for 18 hours. The mixture was diluted with ethyl acetate, washed with water, and concentrated under reduced pressure. The residue was purified by flash chromatography using a hexane:ethyl acetate:methanol gradient to give 6,7-dichloro-2,3-dimethoxy-5-(1,2,4-triazol-1-ylmethyl)quinoxaline (99 mg, 58%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.O>C(Cl)Cl>[N:1]1([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nc2ccccc2o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc2oc(N3CCNCC3)nc2c1
Reaction time: 0.75 h

Procedure:
Anhydrous piperazine (5.6 g) was dissolved in methylene chloride (100 ml) to which was subsequently added triethylamine (4.5 ml). With cooling in an ice bath, to this was added dropwise 2-chlorobenzoxazole (3.7 ml) in small portions, followed by 45 minutes of stirring. The reaction solution was mixed with water, extracted with methylene chloride and then washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. The organic layer was dried with magnesium sulfate and the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (methanol) to obtain the title compound 2-(1-piperazinyl)benzoxazole (4.751 g) in the form of yellow crystalline powder.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[O-2].[Mg+2].O.[CH:13]([O:26][C:27](N=[N+]=[N-])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[CH:13]([O:26][C:27]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:28])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: [N-]=[N+]=NC(=O)OC(c1ccccc1)c1ccccc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(c1ccccc1)c1ccccc1)C(=O)O

Procedure:
To a mixture consisting of 13.1 g. of L-leucine, 6 g. of magnesium oxide, and 150 ml. of water is added a solution of 25.3 g. of benzhydrylazidoformate in 150 ml. of dioxane, and the resulting mixture is stirred at room temperature for 2 days. It is then filtered, and the filtrate is concentrated to remove the dioxane. The aqueous concentrate is acidified with solid citric acid, and the acidified mixture is extracted with ethyl acetate. The extract is dried and evaporated to dryness to give an oily residue of N-benzhydryloxycarbonyl-L-leucine, which is suitable for use without further purification. To a mixture of 32 g. of this intermediate product, 25 g. of pentachlorophenol, and 300 ml. of ethyl acetate, at 5° C., is added 20 g. of dicyclohexylcarbodiimide, and the resulting mixture is kept at 5° C. for 5 hours and filtered. The filtrate is concentrated to small volume, and the concentrate is treated with petroleum ether to give a precipitate of N-benzhydryloxycarbonyl-L-leucine pentachlorophenyl ester, which is isolated and crystallized from ethanol-water; m.p. 84°-86° C.; [α]D25 -27.8° (2% in methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]([CH3:20])([CH3:19])[CH2:9][C:10]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:11](=O)[CH3:12])[CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]2.[Na+].[Cl-].C(OCC)(=O)C>O1CCCC1.[Ti]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]([CH3:20])([CH3:19])[CH2:9][C:10]([C:14]([F:16])([F:17])[F:15])([OH:18])[C:11](=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]3)[CH3:12])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)=O)C(F)(F)F
Reactant: Cc1ccc2c(N)cccc2n1
Agent: [Ti]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)=Nc1cccc2nc(C)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
645 mg (2 mmol) of 5-(5-fluoro-2-methoxyphenyl)-3-hydroxy-5-methyl-3-(trifluoromethyl)hexan-2-one is refluxed in 4 ml of tetrahydrofuran under nitrogen with 0.84 ml (4 mmol) of titanium tetraethylate and 348 mg (2.2 mmol) of 5-amino-2-methylquinoline for 24 hours. After cooling to room temperature, the reaction mixture is stirred into 20 ml of saturated NaCl solution, 50 ml of ethyl acetate is added, and it is stirred for 30 minutes, suctioned off on Celite, and rewashed with ethyl acetate and with tetrahydrofuran. The organic phase is separated, dried (sodium sulfate) and concentrated by evaporation. Chromatography on silica gel with hexane-ethyl acetate yields 578 mg of the product.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:22]1([NH:28][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CCCCC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), cyclohexanamine (131.03 mg, 1.32 mmol, 3.00 equiv), potassium carbonate (304.41 mg, 2.21 mmol, 5.00 equiv), and N,N-dimethylformamide (2 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 20 mL of water. The resulting aqueous solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined and washed with 5×30 mL of aq. sodium chloride. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50). This resulted in 80 mg (46%) of methyl 3-(cyclohexylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:29])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4].[Mn]([O-])(=O)(=O)=[O:40].[K+]>CO.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:29])(=[O:40])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[N:11]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)=O)nc1)n2S(=O)(=O)c1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)nc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (301 mg, 0.55 mmol) in methanol (30 ml) was added a solution of potassium permanganate (88 mg, 0.55 mmol) in water (30 ml). The reaction mixture was stirred at 25° C. for 1 h. The suspension was filtered through a short silica gel pad and then washed with ethyl acetate (3×30 mL). The filtrate was concentrated and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (230 mg, 72%): LC/MS m/e calcd for C28H27N3O6S2 [M+H]+ 566.67, observed 565.9.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:8]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(N(CC)CC)C.CN1CCCC1=O>O>[N+:8]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][NH:18][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCCCC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
121 parts of valeryl chloride are added to a mixture of 181 parts of p-nitrobenzoic acid hydrazide, 101 parts of triethylamine and 1,000 parts of N-methylpyrrolidone, while cooling with ice. The solution is then stirred for a further 4 hours at room temperature, after which it is poured into 5,000 parts of water, and the resulting precipitate is filtered off under suction, washed with water and dried. 250 parts (95% of theory) of N-(p-nitrobenzoyl)-N'-valerylhydrazine of melting point 185°-187° C. are obtained.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>CN(C)C=O>[C:23]([OH:28])(=[O:29])[CH2:24][CH2:25][C:26]([OH:14])=[O:27].[C:7]1([C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[C:7]1([C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)O1
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)O
Reaction time: 8 h

Procedure:
A clean dry reactor of 20 gallon capacity (91 liters) was charged with pyridine (7.0 kg.) followed by dimethylformamide (35.5 kg.). With agitation, benzoin (18.80 kg.) and succinic anhydride (16.0 kg.) were added. The reactor was flushed with nitrogen. Under a continuing atmosphere of nitrogen, the mixture was heated to 90°-95° C. and maintained within this temperature range for 2 hours. The reaction mixture was cooled to 35°-40° C. After twenty minutes, the reaction mixture was tranferred gradually over 5 hours to a mixture of water (190 kg.) and hydrochloric acid of specific gravity 1.18 (28 kg.) at 55°-60° C. in a reactor of 50 gallon capacity (227 liters). The temperature was maintained at 50°-60° C. over the 5 hour period. Dimethylformamide (9.0 kg.) was used for washing through. The mixture was cooled slowly until product crystallised and then to 15° to 20° C. The mixture was stirred overnight at 15° to 20° C. The product was filtered on a ceramic filter and sucked well dry. The product was then washed with water ten times with 20 kg. each time. Ater each wash portion the product was sucked well dry. The product was then dried in a circulating air oven at 50°-60° C. for 12 to 18 hours. The yield obtained was 25.5 kg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12]=O.O.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CCO>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[CH2:12][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=O
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: C1CCNC1
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(CN2CCCC2)c(O)c1
Yield: 29 %

Procedure:
N-(3-hydroxyphenyl)acetamide (0.50 g, 3.31 mmol), formaldehyde 37% in water (678 μL, 2.7 eq), and pyrrolidine (276 μL, 1 eq) were dissolved in 10 mL of EtOH. The reaction mixture was refluxed overnight, evaporated and purified by flash chromatography (DCM/MeOH/NH4OH 9.6:0.4:0.1) to yield expected compound as a pale yellow oil (224 mg, 29% yield). LC-MS: m/z (ESI) 235.13 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:11][N:10]([CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:21]S(N=C=O)(=O)=O.CN(C)C=O>C(COC)OC.O>[Cl:21][C:9]1[N:10]([CH3:20])[CH:11]=[C:12]([S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cn1cc(-c2ccc(Cl)cc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(S(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.2 %

Procedure:
A solution of 3-(p-chlorophenyl)-1-methyl-4-[(trifluoromethyl)sulfonyl]pyrrole (0.5 g, 0.0015 mol) in dimethoxyethane is treated with chlorosulfonyl isocyanate (0.3 mL, 0.0034 mol), stirred for 24 hours at room temperature, treated with additional chlorosulfonyl isocyanate (0.6 mL, 0.0068 mol), stirred for 24 hours, treated with dimethylformamide (2 mL), stirred for one hour, diluted with water and extracted with ether. The combined organic extractes are washed with water, dried and concentrated in vacuo to obtain a semi-solid. Flash chromatography of the semi-solid using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as a white solid (0.2 g, mp 117°-119° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH3:21])[CH:9]=2)=[O:5])[CH3:2].[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.[W]>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21][Br:23])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(C)cc2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(CBr)cc2C1=O
Yield: 36.6 %

Procedure:
6-Methyl-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (3 g, 10.3 mmol) obtained in Step 4 was dissolved in carbon tetrachloride, and N-bromosuccinimide (2 g, 11.4 mmol) and 2,2′-azobisisobutyronitrile (500 mg, 3.09 mmol) were added thereto. The mixture was refluxed for 3 hrs under the irradiation of a 375 W tungsten lamp. Upon the completion of the reaction, the resulting mixture washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 1.4 g of the titled compound (yield: 36.7%) in oil state.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:10]([CH3:22])[C:11](=[O:21])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[N:14]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH:34]2[CH2:36][C@H:31]1[CH2:32][NH:33]2)=[O:29])([CH3:26])([CH3:25])[CH3:24].O>O1CCCC1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH:34]2[CH2:36][C@H:31]1[CH2:32][N:33]2[C:9]1[N:10]([CH3:22])[C:11](=[O:21])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[N:14]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: CC(C)(C)OC(=O)N1CC2C[C@H]1CN2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2C[C@@H]3CC2CN3C(=O)OC(C)(C)C)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A mixture containing 1.95 ml (14 mmol) of triethylamine, 2.45 g (11 mmol) of 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one, 2.58 g (13 mmol) of (1S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in 100 ml of anhydrous tetrahydrofuran was stirred at room temperature for 2 h. Water was added to the cooled mixture and the resulting solution extracted with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 100/0 to 98/2 to afford 4.2 g of pure product as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH3:25][O:26][C:27]1[N:32]=[C:31]2[S:33][C:34]([NH2:36])=[N:35][C:30]2=[CH:29][CH:28]=1>S(Cl)(Cl)=O.N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:36][C:34]2[S:33][C:31]3[C:30]([N:35]=2)=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[N:32]=3)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc2nc(N)sc2n1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc([N+](=O)[O-])cc3)sc2n1
Reaction time: 5 h

Procedure:
The title B compound, 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (7.5 g, 28.5 mmol) is dissolved in 25 mL of thionyl chloride and a drop of DMF and the mixture stirred at RT for 5-6 h. The excess of thionyl chloride is removed under reduced pressure. The residue is then taken up in DCM and added dropwise to a solution of the title E compound in Example 1, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (5.2 g, 28.5 mmol) in 25 mL of pyridine. The reaction mixture is stirred for 5 h before being evaporated to remove the pyridine. The residue is partitioned between ethyl acetate and brine, extracted with ethyl acetate. The combined organic layers are washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and then reduced to an orange-brown solid. This is then vacuum dried to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-(4-nitro-phenyl)-propionamide as a foam: 1H NMR (400 MHz, CDCl3) δ 1.0-1.1 (m, 2H), 1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.6 (t, 1H, J=7.8), 4.01 (s, 3H), 6.8 (d, 1H, J=8.8), 7.4 (d, 2H, J=8.6), 7.8 (d, 1H, J=8.8 Hz), 8.19 (d, 2H, J=8.6 Hz), 9.3 (s, 1H); LC/MS 427 (M+1).