Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12]Cl)=[C:7]([CH3:15])[C:6]([O:16][CH3:17])=[C:5]([O:18][CH3:19])[C:4]=1[O:20][CH3:21].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([O:18][CH3:19])[C:6]([O:16][CH3:17])=[C:7]([CH3:15])[C:8]=1[CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=1.[CH3:1][O:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([O:18][CH3:19])[C:6]([O:16][CH3:17])=[C:7]([CH3:15])[C:8]=1[CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:27][CH:28]=1
Reactant: COc1c(C)c(CC=C(C)CCl)c(OC)c(OC)c1OC
Reactant: COC(=O)Cc1ccc(O)cc1
Product: COC(=O)Cc1ccc(OCC(C)=CCc2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Product: COc1c(C)c(CC=C(C)COc2ccc(CC(=O)O)cc2)c(OC)c(OC)c1OC

Procedure:
Using 1,2,3,4-tetramethoxy-5-methyl-6-(4-chloro-3-methyl-2-butenyl)benzene and methyl p-hydroxyphenylacetate and following the procedure described above, there were obtained methyl 4-[4-(2,3,4,5-tetramethoxy-6-methylphenyl)-2-methyl-2-butenyloxy]phenylacetate (Compound 15) and 4-[4-(2,3,4,5-tetramethoxy-6-methylphenyl)-2-methyl-2-butenyloxy]phenylacetic acid (Compound 16).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH2:19]([N:22]([CH2:26][CH:27]=[CH2:28])[C:23](Cl)=[O:24])[CH:20]=[CH2:21]>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:23]([N:22]([CH2:26][CH:27]=[CH2:28])[CH2:19][CH:20]=[CH2:21])=[O:24])=[N:6][CH:7]=1
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: NNc1ccc(F)cn1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(CC=C)C(=O)NNc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 2.54 g, 20.0 mmol) in DCM (150 mL) and DIPEA (3.87 g, 30.0 mmol) was added N,N-di-2-propen-1-yl-carbamic chloride (for reference procedure see for example Tetrahedron 1996, 52, 13739-13750, which is incorporated herein by reference in its entirety; 4.13 g, 26.0 mmol) and the reaction mixture was stirred at RT for 18 h. The reaction mixture was diluted with MeOH (50 mL) and loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The compound containing fractions were concentrated in vacuo and the resulting residue was purified by FCC on silica, using a gradient of 0-6% [2M NH3 in MeOH] in DCM, to afford the title compound (2.30 g, 46%) as a yellow solid. LCMS (Method 1): Rt 2.26 min, m/z 251 [MH+].
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: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:44][O:45][C:46](=[O:50])[C@H:47]([CH3:49])[NH2:48].CCN(CC)CC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:48][CH:47]([CH3:49])[C:46]([O:45][CH3:44])=[O:50])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26]
Reactant: COC(=O)[C@H](C)N
Reactant: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
To a solution of 3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylic acid (1.0 equiv.) in 50 ml of THF was added N-methylmorpholine (1.0 equiv.) at RT. The reaction mixture was then cooled to −20° C. and isobutylchloroformate (1.0 equiv.) was added and stirred at −20° C. for 5 min. L-alanine methyl ester hydrochloride (1.1 equiv.) was neutralized with Et3N (1.1 equiv.) in 25 ml of THF and added to the above mixture. The mixture was stirred at −20° C. for 5 min and then gradually warmed to RT over a period of 1 hr. THF was evaporated under vacuum and the residue was triturated with EtOAc with minimum quantity of MeOH and collected by filtration. This yielded the title compound as a white solid (92%) after drying in vacuo. 1H NMR (300 MHz, DMSO-d6) δ: 1.38-1.41 (d, J=7.2 Hz, 3H), 2.32 (s, 3H), 3.64 (s, 3H), 4.47-4.51 (t, J=7.2 Hz, 1H), 7.12-7.17 (m, 2H), 7.25-7.32 (m, 1H), 7.61 (S, 1H), 7.67-7.70 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 8.05-8.08 (d, J=8.7 Hz, 1H), 8.34 (s, 1H), 8.67 (s, 1H), 9.35-9.37 (d, J=6.9 Hz, 1H); ms (ESI) m/z 459.1 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-:6])O.[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[CH:41]1[CH2:54][CH2:53][C:44]2([O:48][C:47]([CH3:50])([CH3:49])[C:46]([CH3:52])([CH3:51])[O:45]2)[CH2:43][CH2:42]1>C(OCC)(=O)C>[O:7]=[C:4]1[O:6][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([CH:41]4[CH2:54][CH2:53][C:44]5([O:48][C:47]([CH3:50])([CH3:49])[C:46]([CH3:52])([CH3:51])[O:45]5)[CH2:43][CH2:42]4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[NH:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)(C)C(C)(C)O3)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OC(C)(C)C(C)(C)O3)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.28 g), sodium hydrogen carbonate (0.45 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-oxo-7-propyl-4-(2,2,3,3-tetramethyl-1,4-dioxaspiro[4.5]dec-8-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.052 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.044 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.068 g, 41%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O1CCCC1.[CH3:17][NH2:18]>CO.CCOC(C)=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:18][CH3:17])[N:10]=1
Reactant: CN
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nc(Cl)ccc1C(=O)O
Temperature: 100 °C
Yield: 99.5 %

Procedure:
To a steel autoclave was added 2,6-dichloronicotinic acid (tech.) (30 g, 156.2 mmoles), tetrahydrofuran (30 mL) and monomethylamine (68.2 mL. 33 wt % in ethanol, 500 mmol). The reaction vessel was heated at 100° C. for 4 h. The reaction mixture was cooled and the solution transferred from the autoclave to a 500 mL flask and concentrated under vacuum to give a green solid. The solid was dissolved in 300 mL MeOH and 1.2 L EtOAc, poured into a separatory funnel and washed with 1N HCl (2×300 mL) and brine. The organic solution was then concentrated to dryness to yield 6-chloro-2-(methylamino)nicotinic acid (29 g, 96%) as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=[C:3]1[C:12]([O:14]CC)=[O:13].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C.O.C(OCC)(=O)C>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3]([C:12]([OH:14])=[O:13])=[N:4]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1n[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C(=O)O)c(=O)c3ccccc32)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of ethyl 4-oxo-1,4-dihydrocinnoline-3-carboxylate (2.0 g), potassium iodide (1.5 g) and potassium carbonate (2.5 g) in DMF (50 mL) was added 1-(chloromethyl)-4-methoxybenzene (1.4 mL), and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was dissolved in ethanol-THF (1:1, 30 mL), 1 N aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with water, neutralized with 1 N hydrochloric acid (15 mL), and the precipitate was collected by filtration, washed with water, and dried to give the title compound (1.1 g).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][O:16][CH2:17][CH3:18])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[C:25]([O:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:45]=[CH:44][C:41]([CH2:42][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]=[C:7]2[CH2:15][O:16][CH2:17][CH3:18])=[CH:40][CH:39]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 93.4 %

Procedure:
A procedure similar to that described in Example 82(a) was repeated, except that 315 mg of ethyl 4-(1-hydroxy-1-methylethyl)-2-ethoxymethylimidazole-5-carboxylate [prepared as described in Preparation 44 (iii)], 145 mg of potassium t-butoxide and 510 mg of 4-[2-(t-butoxycarbonyl)phenyl]benzyl bromide were employed and the product was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to obtain 600 mg of the title compound as a syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:27][N:26]=1.[CH2:37]([O:39][C:40](=[O:56])[CH:41]([O:43][P:44]([CH2:53][CH:54]=O)([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:45])[CH3:42])[CH3:38].[BH3-]C#N.[Na+]>C(O)(=O)C.CN(C=O)C>[CH2:37]([O:39][C:40](=[O:56])[CH:41]([O:43][P:44]([CH2:53][CH2:54][N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:9](=[O:23])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:24][C:25]4[N:30]=[C:29]([C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)[CH:28]=[CH:27][N:26]=4)[CH:4]=3)=[CH:15][CH:14]=2)[CH2:22][CH2:21]1)([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:45])[CH3:42])[CH3:38]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CCOC(=O)C(C)OP(=O)(CC=O)Oc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)OP(=O)(CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1)Oc1ccccc1
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
A solution of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide (20 mg, 0.04 mmol) and 2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester (60 mg, 0.2 mmol) in 1% Acetic Acid/DMF (1.5 mL) solution was stirred at room temperature for 7 hours followed by an addition of NaCNBH3 (30 mg, 0.24 mmol). The resulting mixture was stirred for additional 30 min when completion of the reaction was observed by LCMS. After evaporation of solvent, the residue was taken up in CH2Cl2 and then extracted with saturated aqueous NaHCO3 The organic extracts were dried in vacuo and the residue was purified by silica gel chromatography using MeOH—CH2Cl2 (7%) to afford 8 mg (26%) of the product. 31P NMR (121.4 MHz, CDCl3) δ 27.2, 28.6; MS (m/z) 764 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: NC1CCCCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(NC2CCCCC2)c2nccn12
Temperature: 90 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
Intermediate 2 (5,8-Dibromoimidazo[1,2-a]pyrazine, 200 mg, 0.72 mmol), cyclohexylamine (86 mg, 0.86 mmol) and di-isopropylethylamine (140 mg, 0.74 mmol) are suspended in iso-propanol (5 ml). The mixture is stirred at 90° C. for 18 h. The solvent is evaporated in vacuo and the residue dissolved in dichloromethane (5 mL). The organic layer is washed with saturated NaHCO3(aq) (10 ml), H2O (10 ml) and brine (10 mL). The organic layer is dried (MgSO4) and evaporated in vacuo. The oily residue is purified by column chromatography, eluting with 5:1 hexane:ethyl acetate to give a brown oil (147 mg, 69%). 1H-NMR (400 MHz, d6-DMSO) =1.22-1.29 (m, 1H), 1.32-1.49 (m, 4H), 1.64 (d, 1H, J=15.2 Hz), 1.77 (d, 2H, J=12.8 Hz), 1.92 (d, 2H, J=15.2 Hz), 3.97-4.01 (1H, m), 7.33 (d, 1H, J=8.4 Hz), 7.48 (s, 1H), 7.63 (s, 1H), 7.92 (s, 1H). LCMS: Rt 3.83 min (99.8%), m/z (APCI) 295 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:18][C:19]1[C:27]2[N:26]=[C:25](Cl)[NH:24][C:23]=2[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1>>[Br:18][C:19]1[C:27]2[N:26]=[C:25]([N:15]3[CH2:16][CH2:17][N:12]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=4)[CH2:13][CH2:14]3)[NH:24][C:23]=2[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Product: FC(F)(F)c1cnc(N2CCN(c3nc4c(Br)cc(C(F)(F)F)cc4[nH]3)CC2)c(Cl)c1

Procedure:
The reaction of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine (212 mg, 0.8 mmol, ABCR) and 4-bromo-2-chloro-6-trifluoromethyl-1H -benzoimidazole (210 mg, 0.7 mmol, Example 6b) under the conditions of Example 3c afforded the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 530 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1.CN(C)[CH:24]=[O:25]>O1CCCC1.C(O)(=O)C>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([CH:24]=[O:25])=[C:16]([F:21])[CH:15]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cc(Br)cc1F
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A solution of diisopropylamine (194.4 mmol) in tetrahydrofuran (350 mL) was cooled in an ice/water bath as n-BuLi (69.5 mL of a 2.5 M solution in hexanes) was added slowly via syringe. After 30 minutes, the solution was cooled in a dry ice/acetone bath as 1-bromo-3,5-difluorobenzene (173.7 mmol in 50 mL of tetrahydrofuran) was added gradually over the course of 25 minutes. After stirring for 30 minutes, dimethylformamide (208.4 mmol) was added gradually to the reaction mixture over the course of 30 minutes. After stirring for 2 hours more in the cooling bath, acetic acid (35 mL) was added, the cooling bath removed, and water (500 mL) was added. The reaction mixture was then extracted with ether (1 L), and the organic phase was washed with 1 N HCl (250 mL), brine, dried over magnesium sulfate and filtered. After condensing the organic phase with a rotary evaporator, the resulting brown solid was tritrated with hexanes before filtration to afford the title compound (I-1a) as a colorless solid (37.8 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=O)(C)(C)C.[CH2:16]([O:23][C:24]([NH:26][C:27](=[NH:30])SC)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]([NH:26][C:27]([N:13]1[CH2:14][CH2:15][CH:11]([CH2:10][CH2:9][NH2:8])[CH2:12]1)=[NH:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CCN)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67529.2 %

Procedure:
2.18 g (0.0102 mmole) (3RS)-3-(N-tert-butyloxycarbonylaminoethyl) pyrrolidine and 2.81 g (0.0125 mole) N-benzyloxycarbonyl-S-methylisothiourea was dissolved in 30 ml toluene and heated to 60°-70° C. for eight hours followed by stirring at room temperature for one day. 0.3M KHSO4 -solution was added and the water layer was washed with a mixture of the toluene and ethyl acetate and left for 2 days under which time the Boc group was removed. The acidic water phase was made alkaline and extracted four times with CH2Cl2 The combined organic layer was dried (Na2SO4), filtered and evaporated to yield 2.0 g (51%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:19]=1[O:20][CH3:21])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9]1)=[O:7])#[N:2].ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:19]=1[O:20][CH3:21])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:34])[CH2:9]1)=[O:7])#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1c(C#N)cc(C(=O)N2CS(=O)c3ccccc32)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiazole (594 mg) was dissolved in chloroform (10 mL), and 70% metachloroperbenzoic acid (433 mg) was added to the solution, and then the mixture was stirred at 0° C. for 5 minutes. The organic solvent was distilled off under reduced pressure, and then 1N sodium hydroxide was added and the precipitated crystal was washed with 1N sodium hydroxide and water to obtain the title compound (619 mg) as a colorless crystal.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[N:12]=[CH:11][N:10]=1
Reactant: c1c[nH]cn1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-n2ccnc2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of sodium hydride (0.65 g, 55% dispersion in oil, pre-washed with petrol) in dry DMF (5 ml) at 10°-15° C. under nitrogen, was added a solution of imidazole (1.02 g, 15 mmol) over five minutes. The reaction mixture effervesced and an exotherm took place. After stirring for 11/2 hours at room temperature, the cloudy solution was added drop-wise over one hour to a solution of 4,6-dichloropyrimidine in dry DMF (10 ml) at 0° C. for one hour, added to water and then extracted with ether (×3). The combined ether extracts were washed with dilute sodium hydroxide solution and water (×3) and then dried. Concentration under reduced pressure gave 4-chloro-6-(imidazol-1-yl)pyrimidine as a pale yellow solid (1.00 g); m.p. 122°-4° C., which was used without further purification.
Reaction SMILES: [OH-].[Na+:2].[N:3]1([C:9]2[N:10]=[C:11]([CH2:16][C:17]([O:19]CC)=[O:18])[NH:12][C:13](=[O:15])[CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>O1CCCC1>[N:3]1([C:9]2[N:10]=[C:11]([CH2:16][C:17]([O-:19])=[O:18])[NH:12][C:13](=[O:15])[CH:14]=2)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1.[Na+:2]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
18.7 ml of 2M sodium hydroxide are added to a solution of 10 g of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate described in example 6a (step (2′a)a) in 300 ml of tetrahydrofuran. The reaction mixture is stirred for 48 hours at ambient temperature. The precipitate formed is filtered off through sintered glass, washed with ethyl acetate and rinsed several times with ethyl ether. The solid obtained is then dried in a rotary evaporator so as to give 8.7 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.[NH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[N:3]=[CH:4][C:5]=2[C:18]2[CH:19]=[N:14][CH:15]=[N:16][CH:17]=2)[N:10]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1nc(N)cs1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: Cc1ccc2c(-c3cncnc3)cnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=335.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 5-pyrimidineboronic acid and 4-amino-2-methylthiazole (Example F).