Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]1([CH3:44])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]2[CH2:30][C:29]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])([CH:37]=O)[CH2:28][C:27]1=2.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:37][C:29]1([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:28][C:27]2[C:26]([CH3:25])([CH3:44])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]=2[CH2:30]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCC1(C=O)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCC1(C=C(Br)Br)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4.9 g of carbon tetrabromide were dissolved in 75 ml of methylene chloride and treated dropwise with a solution of 7.7 g of triphenylphosphine in 80 ml of methylene chloride at a temperature of −20° C. The slightly orange solution was stirred at 0° C. for 15 minutes, then treated with a solution of 2 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbaldehyde in 20 ml of methylene chloride. the reaction mixture was stirred at room temperature for 2 hours, then poured on ice/water and diluted aqueous sodium bicarbonate solution and extracted with methylene chloride. The yellow oil which was received after drying of the organic phase and evaporation of the solvent, was further purified with flash chromatography (silica gel, hexane/ethyl acetate=20:1) to give 2-(2,2-dibromo-vinyl)-4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene as a slightly yellow oil.
Reaction SMILES: [CH2:1]([C:5]1([CH3:8])[CH2:7][O:6]1)[CH2:2][CH2:3][CH3:4].[CH2:9]([Li])[CH2:10]CC.[H-].[Na+].O1CC1.[C-]#[C-].[Li+].[Li+].C(N)CN>>[CH3:8][C:5]([OH:6])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][C:9]#[CH:10]
Reactant: [Li]CCCC
Reactant: CCCCC1(C)CO1
Agent: [C-]#[C-]
Agent: [H-]
Agent: [Li+]
Solvent: NCCN
Solvent: C1CO1
Product: C#CCC(C)(O)CCCC

Procedure:
A fourth alternative procedure is typified by the formation of the 2-butyl-2-methyloxirane with n-butyl lithium or sodium hydride and reaction of this oxirane with lithium acetylide-ethylenediamine to directly produce the 4-methyl-1-octyn-4-ol as shown by reaction procedure (IIIb) of Scheme (I).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[S:9]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:14]([C:13]2[S:9][C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[CH:12]=2)(=[O:15])=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(N)c1C
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1noc(NS(=O)(=O)c2cc3ccccc3s2)c1C
Yield: 60 %

Procedure:
3,4-Dimethyl-5-amino-isoxazole (0.224 g, 2.0 mmol) and 50 mg of DMAP were stirred in 5 ml of pyridine at 25° C. The benzo[b]thiophene-2-sulfonyl chloride (0.16 g, 2.6 mmol) was added and the dark brown-yellow reaction mixture was poured into 100 ml of ethyl acetate and washed with 2% HCl (3×50 ml). The organic phase was dried with MgSO4, filtered and concentrated to collect 0.61 g of a brown oil/solid. The brown oil/solid was subjected to flash chromatography (30% ethyl acetate/hexanes) to provide 0.37 g of a light brown solid. This was stirred in 10 ml of methanol and 0.5 g of NaOH. The methanolic solution was heated for reflux for 1 h, then cooled to 25° C. and the methanol was removed in vacuo. The resulting residue was acidified to pH 1 with 2% HCl (100 ml) and extracted with ethyl acetate (2×50 ml) The organic phase was dried with MgSO4, filtered and concentrated to collect 0.225 g of a yellow-orange solid. This was recrystallized from CHCl3 /Hexanes to produce a light tan-yellow solid (0.194 g, 31% yield), m.p. 157°-160° C.
Reaction SMILES: N1C2C(=CC=CC=2)C=NC=1.[NH2:11][C:12]1[N:21]=[C:20]([NH2:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[O:31]C)[C:18]=2[Cl:23])[N:13]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:11][C:12]1[N:21]=[C:20]([NH2:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[OH:31])[C:18]=2[Cl:23])[N:13]=1
Reactant: COc1ccc(Cl)cc1-c1ccc2nc(N)nc(N)c2c1Cl
Agent: BrB(Br)Br
Agent: c1ccc2ncncc2c1
Solvent: ClCCl
Product: Nc1nc(N)c2c(Cl)c(-c3cc(Cl)ccc3O)ccc2n1

Procedure:
A series of quinazoline analogs may be prepared from the above 2,4-diamino-5-chloro-6-(5-chloro-2-methoxyphenyl)quinazoline. This is accomplished by the reaction of 2,4-diamino-5-chloro-6-(5-chloro-2-methoxyphenyl)quinazoline with 1M boron tribromide in methylene chloride, yielding the corresponding 2,4-diamino-5-chloro-6-(5-chloro-2-hydroxyphenyl)quinazoline. The hydroxy intermediate in turn is reacted with a halogen-containing compound and potassium carbonate in N,N-dimethylformamide, affording the appropriately 6-(5-chloro-2-substituted-phenyl)quinazoline, for example, 2,4-diamino-5-chloro-6-[5-chloro-2-(pyridin-2-ylmethoxy)phenyl]quinazoline. Example 3 describes in detail the preparation of this compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[O:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:21][C:22]2[O:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(F)cc2)C1Cc1ccc(C(F)(F)F)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To 1,1-dimethylethyl (4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-((5-(trifluoromethyl)-2-furanyl)methyl)-1,3-oxazolidine-3-carboxylate (1.91 g, 4.45 mmol) in methanol (10.7 ml) was added a methanol solution (10.7 ml, 5.35 mmol) of 0.5N sodium hydroxide under ice-cooling and the mixture was stirred at room temperature for 10 min. Water (50 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.79 g, 100%).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH2:17][CH2:18][C:12]2([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([C:12]23[CH2:18][CH2:17][CH2:16][CH2:15][CH:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11]3)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(C23CCCCC2CN(Cc2ccccc2)CCO3)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc(C23CCCCC2CNCCO3)c1

Procedure:
16 g (0.045 mole) of 4-benzyl-9a-(3-methoxyphenyl)-perhydro-1,4-benzoxazepine (boiling point 240°-260° C./0.07 mbar), prepared by methods similar to that of Example 1, are hydrogenated in the conventional manner with a palladium/charcoal catalyst (5 g of 5% strength Pd on charcoal) in glacial acetic acid; after filtration and distillation, 8.8 g (75% of theory) of 9a-(3-methoxyphenyl)-perhydro-1,4-benzoxazepine, of boiling point 180°-185° C./0.07 mbar, are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: CC(C)CCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OCCC(C)C)c1
Yield: 88 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 646.5 μl (5.181 mmol) of isopentyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1 and 50/1) to obtain 8.2 mg (0.456 mmol, 88%) of 2-isopentyloxy-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.[C:11]1(Cl)[C:17](=O)C(Cl)=C(Cl)[C:13](=O)[C:12]=1Cl.C(=O)/C=C/C>CC(O)CC.O>[F:9][C:8]1[CH:7]=[C:6]2[C:4](=[CH:3][C:2]=1[F:1])[N:5]=[C:12]([CH3:13])[CH:11]=[CH:17]2
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: C/C=C/C=O
Agent: Cl
Solvent: CCC(C)O
Solvent: O
Product: Cc1ccc2cc(F)c(F)cc2n1

Procedure:
25.0 g of 3,4-difluoroaniline are dissolved in 120 of 2-butanol. 50 ml of a saturated solution of hydrogen chloride in 2-butanol are added slowly and afterwards 47.6 g (0.1936 mol) of p-chloranil are also added. With a good stirring and at reflux temperature (100-110° C.) a solution of 19.4 ml (0.236 mol) of crotonaldehyde in 45 ml of butan-2-ol is dropped slowly (ca. 2 hr). The whole is refluxed for two additional hours and then evaporated to dryness. The residue is taken with excess THF and is filtered and washed thoroughly with THF until the filtering appears to be uncoloured. The solid thus obtained is solved in water, filtered from some solid impurities and washed with ethyl ether. The aqueous layer is made slightly alkaline with 2N NaOH solution and then extracted with diethyl ether. The ethereal layer is dried and treated with a little decolourising charcoal. After evaporation a white solid is obtained (22.7 g, 65%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:15]2[S:25][C:18]3[N:19]([CH3:24])[C:20]([CH2:22][OH:23])=[CH:21][C:17]=3[CH:16]=2)=[N:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([C:3]1[C:4]([C:15]2[S:25][C:18]3[N:19]([CH3:24])[C:20]([CH:22]=[O:23])=[CH:21][C:17]=3[CH:16]=2)=[N:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1cc2cc(CO)n(C)c2s1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1cc2cc(C=O)n(C)c2s1
Yield: 71.4 %

Procedure:
To solution of methyl 5-ethyl-6-(5-(hydroxymethyl)-6-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-2-methoxynicotinate (0.233 g, 0.75 mmol) in DCM (8 mL) was added activated MnO2 (0.60 g+0.60 g+0.30 g, 6.20+6.20+3.10 mmol) in 3 portions with 30 min intervals. Reaction was monitored by LC/MS. Upon complete consumption of starting material MnO2 was filtered and washed with DCM. Mother liquor was concentrated affording methyl 5-ethyl-6-(5-formyl-6-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-2-methoxynicotinate (0.192 g, 82%) as solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:10]Br>CC(O)=O>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ncccc1CO
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1CO
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a stirred solution of 2-amino-3-(hydroxymethyl)pyridine (15.0 g, 121 mmole) in HOAc (300 mL) at RT was added bromine (6.2 mL, 121 mmole) dropwise over 1 hr. A suspension formed after approximately 15 min. After the addition, the reaction was stirred for an additional 1 hr, then was concentrated under vacuum. The residue was taken up in 1.0 M Na2CO3 (500 mL), and the solution was extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The resulting residue was triturated with a small volume of petroleum ether, filtered and dried under vacuum to give the title compound (18.45 g, 75%) as a beige solid: LCMS (ES) m/e 203.2 (M+H)+; 1H NMR (400 MHz, DMSO-d$) δ 7.89 (d, J=2.3 Hz, 1H), 7.52 (s, 1H), 5.92 (br s, 2H), 5.29 (br s, 1H), 4.30 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][C:10]([CH3:20])=[N:11][C:12]=1[NH:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]1[N:13]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:12]2[C:7]([N:6]=1)=[C:8]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)[N:9]=[C:10]([CH3:20])[N:11]=2
Reactant: CN1CCNCC1
Reactant: Cc1nc(Cl)c(NC(=O)c2ccccc2Cl)c(NC2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(C3CCOCC3)c2n1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
Combine 2-chloro-N-(4-chloro-2-methyl-6-(tetrahydro-2H-pyran-4-ylamino)-pyrimidin-5-yl) benzamide (45.0 g, 118.0 mmol), 1-methylpiperazine (23.0 mL, 207.0 mmol), di-isopropylethylamine (23.0 mL, 131.9 mmol) and isopropyl alcohol (225 mL) in a 1 L Parr reactor. Seal the reactor, start stirring, and adjust the set-point for heat control to 160° C. After the internal temperature reaches 160° C., stir the mixture for 24 hours. Cool the reactor contents to 60° C., vent the vessel of pressure, and transfer the contents to a 2 L flask equipped with overhead stirring apparatus. Rinse out reactor flask with isopropyl alcohol (25.0 mL) and combine the rinse with main solution. Add cold, de-ionized water (780 mL) to the mixture over 30 minutes and stir the resulting precipitate for 30 minutes. Filter the mixture, wash the solids with de-ionized water (2×270 mL) and pull dry on the funnel Further dry the product overnight at 45° C. to afford the 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-1-yl)-9-(tetrahydro pyran-4-yl)-9H-purine as an off-white solid (44.8 g) MS (m/z): 427/429 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[N:8]=2)=[C:4]([F:20])[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2([C:34](O)=[O:35])[CH2:33][CH2:32]2)=[O:30])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:14]([NH:13][C:9]1[N:8]=[C:7]([O:6][C:5]2[C:4]([F:20])=[CH:3][C:2]([NH:1][C:34]([C:31]3([C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)=[O:30])[CH2:33][CH2:32]3)=[O:35])=[C:18]([F:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1nccc(Oc2cc(F)c(N)cc2F)n1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nccc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a solution of Example A3 (300 mg, 1.07 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (240 mg, 1.07 mmol) (as prepared in Example B1) in DMF (20 mL) was added HATU (440 mg, 3.2 mmol) and DIEA (280 mg, 2.1 mmol) in portions. The reaction mixture was stirred at 60° C. under nitrogen overnight. After cooling to room temperature water (30 mL) was added and the solution was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (3×50 mL), dried over sodium sulfate, and concentrated. The crude product was purified by preparative HPLC to give N-(4-(2-acetamidopyrimidin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (42 mg, 8% yield) as a white solid. 1HNMR (300 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.40 (s, 1H), 9.75 (s, 1H), 8.49-8.51 (d, J=5.7 Hz, 1H), 7.94-8.01 (dd, J=12.3 Hz, J=8.1 Hz, 1H), 7.48-7.60 (m, 3H), 7.05-7.16 (m, 2H), 6.83-6.84 (d, J=5.4 Hz, 1H), 1.92 (s, 3H), 1.53-1.59 (d, J=19.2 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.Cl[CH2:27][C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([CH2:27][C:28]3[N:29]=[C:30]([NH2:33])[S:31][CH:32]=3)[CH2:23][CH2:24]1)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1nc(CN2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cs1
Yield: 71.5 %

Procedure:
A suspension of 1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.5 g) obtained in Example 3a), 4-chloromethyl-1,3-thiazol-2-amine hydrochloride (0.76 g) and potassium carbonate (1.12 g) in acetonitrile (50 mL) was refluxed for 4 hours, and then the solvent was distilled off under reduced pressure. The residue was diluted with potassium carbonate, and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with a basic silica gel column to give the title compound (1.4 g) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:12].[NH2:21][CH2:22][CH2:23][NH2:24]>C(O)(C)C>[NH2:21][CH2:22][CH2:23][NH:24][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:12]
Reactant: NCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cc2ccccc2)c1
Solvent: CC(C)O
Product: NCCNc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cc1ccccc1

Procedure:
16.0 g of benzyl 2-chloro-5-nitrophenyl sulphone and 12.0 g of 1,2-diaminoethane are refluxed in 100 ml of isopropanol for one hour. The reaction mixture is cooled down, and the solids are filtered off with suction, are washed with 50 ml of water and are dried. This gives 19.2 g of pale yellow [2-(2-aminoethyl)-amino-5-nitrophenyl]-benzyl sulphone.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[C:26](O)(=[O:28])[CH3:27]>[O-]CC.[Na+]>[CH2:26]([O:28][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)[CH3:27]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: CC(=O)O
Agent: CC[O-]
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc2nc(OCC)ncc2c(=O)[nH]1

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.50 g) in sodium ethoxide solution (from sodium, 0.16 g, and ethanol, 25 ml) was stirred at ambient temperature for 1.5 hours. Cooling and acidification of the reaction mixture with glacial acetic acid (0.42 g) yielded a precipitate which was twice recrystallized from ethanol to yield the title compound, 0.29 g, m.p. 196-197.5° C.
Reaction SMILES: F[B-](F)(F)F.C[O+](C)C.[Cl:10][C:11]1[C:12]([CH3:27])=[C:13]([C:18]([N:20]2[CH2:25][CH2:24][NH:23][C:22](=O)[CH2:21]2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17].[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]([NH:35][NH2:36])=O.C(O)CCC>ClCCl>[Cl:10][C:11]1[C:12]([CH3:27])=[C:13]([C:18]([N:20]2[CH2:25][CH2:24][N:23]3[C:33]([C:29]4[S:28][CH:32]=[CH:31][N:30]=4)=[N:35][N:36]=[C:22]3[CH2:21]2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: NNC(=O)c1nccs1
Reactant: Cc1c(C(=O)N2CCNC(=O)C2)ccc(F)c1Cl
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCCCO
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCn3c(nnc3-c3nccs3)C2)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
Trimethyloxonium tetrafluoroborate (138 mg, 0.887 mmol) was added under argon to a suspension of 4-[(3-chloro-4-fluoro-2-methylphenyl)carbonyl]-2-piperazinone (I59) (200 mg, 0.739 mmol) in dry dichloromethane (DCM) (3.694 ml). The reaction mixture was stirred at room temperature overnight—cloudy mixture. 1,3-thiazole-2-carbohydrazide (I51) (159 mg, 1.108 mmol) was added and the resulting mixture was stirred at room temperature 2 h—reaction mixture was in solution before that a precipitate had appeared. 1-Butanol (3.69 ml) was added—mixture went into solution—and the reaction mixture was stirred at reflux 2 h. The reaction mixture was cooled down to room temperature and DCM was removed in vacuo. The reaction mixture was heated at reflux for 2 h and left at room temperature overnight. The mixture was diluted with DCM (150 mL) and washed with sat. NaHCO3 (2×25 mL), water (25 mL) and brine (25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. NMR: lots of butanol left. The crude product was dissolved in DCM (150 mL) and washed with water (25 mL, 50 mL) and brine (25 mL). The resulting DCM layer was dried over MgSO4 and concentrated under reduced pressure. The foam residue was triturated with Et2O to afford a yellow solid (143.3 mg). The crude product was purified by MDAP (High pH). The obtained solid was dried at 50° C. under vacuum for 1.5 days. The solid was triturated with hexane to get remove the methanol and dried under vacuum at 50° C. to afford the desired product in 75.36 mg as a cream solid.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)=[O:29].[OH-].[K+]>C1COCC1.CO>[C:33]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:35][C:30]([C:28]([NH:27][C:5]2[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:21][CH:22]=3)[CH:8]=[CH:9][C:4]=2[C:3]([OH:42])=[O:2])=[O:29])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1NC(=O)c1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(/C=N/OCCCOc2ccc(C(=O)O)c(NC(=O)c3ccc(-c4ccccc4)cc3)c2)cc1
Yield: 63616.1 %

Procedure:
The desired product was prepared using a procedure similar to Step 7 of example 34. Thus, 2-[(1,1′-biphenyl-4-ylcarbonyl)amino]4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.253 g, 0.448 mmol) was reacted with 1N KOH (0.90 ml) in THF/MeOH (6 ml/4 ml) to give 2-[(1,1′-biphenyl-4-ylcarbonyl)amino]-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid (0.157 g, 0.285 mol, 64%) as a white solid, mp 155-158.5° C. 1H NMR (DMSO-d6) δ 1.25 (s, 9H), 2.14-2.18 (m, 2H), 4.21 (t, J=6.3 Hz, 2H), 4.28 (t, J=6.3 Hz, 2H), 6.78 (dd, J=2.4, 8.9 Hz, 1H), 7.38-7.45 (m, 3H), 7.49-7.54 (m, 4H), 7.77 (d, J=8.3 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 7.98-8.06 (m, 3H), 8.22 (s, 1H), 8.46 (d, 2.4 Hz, 1H) 12.60 (s, 1H); IR (solid) 3120, 2960, 1620, 1580, 1220 and 1140 cm−1; [ES(+)], m/z 551 (M+H)+; Anal. Calcd. for C34H34N2O5: C, 74.16; H, 6.22; N, 5.09, Found: C, 73.94; H, 5.91; N, 4.93.