Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:40][CH3:41])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35](O)=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1.C(OC1C=C(OC2CC3C(C(=O)N(C)CCCCC=CC4C(C([NH:77][S:78]([CH:81]5[CH2:83][CH2:82]5)(=[O:80])=[O:79])=O)(NC3=O)C4)C2)C2C(=C(C)C(OC)=CC=2)N=1)C>>[Br:1][C:2]1[C:3]([O:40][CH3:41])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([NH:77][S:78]([CH:81]4[CH2:83][CH2:82]4)(=[O:80])=[O:79])=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(Br)c2n1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(Br)c2n1

Procedure:
The title compound (7) was prepared from 17-[8-bromo-2-ethoxy-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (6) following the procedure reported for synthesis of N-[17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (3): m/z=734 (M+H)+.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O:18]1[CH2:20][CH2:19]1>>[CH2:1]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][O:16][CH2:20][CH2:19][OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1CO1
Reactant: CCCCCCCCCCNC(=O)CCCO
Product: CCCCCCCCCCNC(=O)CCCOCCO
Reaction time: 2 h
Yield: 97.8 %

Procedure:
In a steel autoclave, 243 grams (1 mole) of N-decyl-4-hydroxy-butyramide at a temperature of 130° C. was admixed with 44 grams (1 mole) of oxirane which was added to the autoclave as a compressed gas. The reaction mixture was stirred and autogenous pressure caused a drop in pressure during the reaction. After the reaction was complete in a period of about 2 hours, 281 grams of product were obtained. The product was then cooled to room temperature whereupon a light solid having a melting point of 48° C. was obtained. IR=6.11 mu.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:12]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:20][CH2:21]2)[CH:30]=[CH:29][CH:28]=1)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCC3)CC2)c1

Procedure:
Example 106 was prepared from 1-(4-chlorophenyl) cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 2H), 7.32–7.23 (m, 6H), 6.95 (d, 1H, J=7.6 Hz), 6.53 (br s, 1H), 3.29 (dd, 2H, J=6.0, 12.4 Hz), 2.93 (d, 2H, J=10.8 Hz), 2.86–2.79 (m, 2H), 2.48–2.41 (m, 3H), 2.37–2.30 (m, 4H), 2.07 (m, 1H), 1.98–1.61 (m, 11H), 1.01 (t, 3H, J=7.6 Hz); ESMS m/e: 496.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[Cl:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:7][C:6]1[O:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(Cl)o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)o1
Yield: 55.1 %

Procedure:
A solution of methyl 4-bromo-5-chloro-2-furancarboxylate (1.1 g, 4.59 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.05 g, 5.05 mmol) [prepared according to Preparation 7], potassium carbonate (3.17 g, 22.97 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.117 g, 0.23 mmol) in 1,4-dioxane (19.14 ml) and water (3.83 ml) was stirred at 80° C. in a sealed tube for 1 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (800 mg, 2.53 mmol, 55% yield) as a yellow oil: LCMS m/e ES 240, 242 (M, M+2)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH:5]([OH:10])[C:6]([F:9])([F:8])[F:7].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>C1COCC1>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:10][CH:5]([C:6]([F:9])([F:8])[F:7])[C:4]([F:12])([F:11])[F:3])=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC(C(F)(F)F)C(F)(F)F)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
2.45 g (61.2 mmol) of sodium hydride was introduced to 15 ml of THF and cooled to 5° C., and then 10.6 g of 1,1,1,3,3,3-hexafluoro-2-propanol was added dropwise thereto. The resulting solution was stirred at 5° C. for 30 minutes, and then 5.0 g of 2-chloro-5-nitropyridine dissolved in 10 ml of THF was added dropwise thereto and stirred at room temperature for 3 hours. The reaction solution was allowed to stand at room temperature for 3 days, the water was added thereto, and the mixture was extracted with ethyl acetate and then washed with saturated salt water. The resultant was dried over anhydrous magnesium sulfate, and then the solvent was removed under a reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography (n-hexane AcOEt=10:1) to obtain 8.4 g of the desired product (Yield: 92%) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[C:24]([S:35][CH3:36])=[N:25][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27]=1[NH2:28])=O)C.O>O=S(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:21](=[O:20])[C:23]3[C:24]([S:35][CH3:36])=[N:25][N:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:27]=3[N:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)c1c(SC)nn(-c2ccccc2)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CSc1nn(-c2ccccc2)c2nc(-c3ccc(Br)cc3)n(-c3ccc(Cl)cc3)c(=O)c12
Temperature: 150 °C

Procedure:
A mixture of 4-bromo-N-(4-chloro-phenyl)-benzamide (1.14 g, 3.67 mmol) in SOCl2 (4.5 mL) is heated to 80° C. for 2 h before SOCl2 is removed in vacuo. The resulted imidoyl chloride intermediate is dissolved in anhydrous dichloroethane (18 mL) and transferred into a sealed tube. After adding 5-amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.12 g, 4.04 mmol) and TiCl4 (0.80 mL, 7.3 mmol), the reaction tube is sealed and heated at 150° C. overnight. After cooling down to room temperature the reaction mixture is poured into water (200 mL) and extracted with chloroform (3×100 mL). The organic layers are combined, washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography to provide 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as a white solid product; HPLC-MS calculated for C24H16BrClN4OS (M+H+) 523.0, found 523.0.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]1([CH2:10][C:11]([CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>N1C=CC=CC=1.C(O)C>[N:2](=[C:11]([CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: NO
Reactant: O=C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CC(Cc1ccccc1)=NO
Yield: 29.8 %

Procedure:
A mixture of hydroxylamine hydrochloride (9 g.) and a solution of 1-phenyl-3-phthalimidoacetone (23.4 g.) in pyridine/ethanol (80 ml.-80 ml.) was stirred at ambient temperature for 3 days. The resulting solution was concentrated, the residue washed twice with a mixture of toluene and methylene chloride and dried. The residue was purified by column chromatography on activated silica gel using cyclohexane/EtOAc 7:3 v/v as eluant to give 2-oximino-1-phenyl-3-phthalimidopropane (7.35 g.) as a mixture of syn and anti isomers.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([NH:4][C:5]1[C:13]([N+:20]([O-:22])=[O:21])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 83b from 4-acetylamino-2-fluoro-benzoic acid, conc. sulphuric acid and conc. nitric acid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:9]=2[N:8]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]1=[O:30])C.[OH-].[Na+].O.Cl>C(O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:9]2[N:8]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7](=[O:30])[N:6]([CH2:5][C:4]([OH:31])=[O:3])[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:10]=2[CH:20]=1
Reactant: CCOC(=O)CN1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)CN1C(=O)N(CC(=O)O)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To a solution of 7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2-dihydro-2-oxo-3H-1,3,4-benzotriazepine-3-acetic acid ethyl ester obtained in Example 56 (0.16 g) in ethanol (3 ml) was added a 1N aqueous solution of sodium hydroxide (0.3 ml). The mixture was stirred for 4 hours at room temperature. To the reaction mixture was added water (50 ml), which was made acid with 1N HCl, then the solution was concentrated. To the concentrate was added dichloromethane (50 ml), which was washed with water, then the solvent was distilled off. The residue was recrystallized from dichloromethane--petroleum ether to give 91 mg of colorless crystals, m.p. 181°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7]([CH3:17])[C:4]=1[CH:5]=[O:6].Br[C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:29][CH2:28][CH2:27][O:26]2)=[CH:21][CH:20]=1.[Mg].O>C1COCC1>[OH:6][CH:5]([C:4]1[C:7]([CH3:17])=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:26][CH2:27][CH2:28][O:29]2)=[CH:21][CH:20]=1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C(O)c2ccc(C3OCCO3)cc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
To an ice-cold solution of 2,3,4,5-tetramethoxy-6-methylbenzaldehyde (5.03 g, 20.94 mmol) in THF (200 ml) was added dropwise a Grignard reagent prepared from 2-(4-bromophenyl)-1,3-dioxolane (12.0 g, 52.4 mmol) and magnesium (1.40 g, 57.6 mmol), and then stirred at room temperature for 4 hours. The reaction mixture was poured into water and was extracted with ether. After the extract was washed with water and dried, and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1) to yield the title compound (7.80 g, 20.0 mmol, yield 96%).
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[C:10]([C@@H:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C@H:18]2[C:30]([O:32]CC)=[O:31])=[CH:9][C:8]1=[O:35].[OH-].[Li+]>CO>[CH3:29][C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C@@H:17]([C:10]2[C:11]([O:13][CH2:14][O:15][CH3:16])=[CH:12][N:7]([CH3:6])[C:8](=[O:35])[CH:9]=2)[C@H:18]([C:30]([OH:32])=[O:31])[CH2:19]1)=[O:24])([CH3:27])[CH3:28]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc(=O)n(C)cc1OCOC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCOc1cn(C)c(=O)cc1[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 3:2 (v/v) THF:MeOH solution (0.04 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(1-methyl-5-{[(methyloxy)methyl]oxy}-2-oxo-1,2-dihydro-4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added lithium hydroxide (1 M aq. solution, 3 eq.). The resulting cloudy solution was stirred vigorously at RT for 24 h. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and 10% aq. HCl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a pink solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]2[CH:9]=[C:10]([C:14](O)=[O:15])[C:11](=[O:13])[O:12][C:7]=2[C:6]=1[O:19][C:20](=[O:22])[CH3:21])(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]2[CH:9]=[C:10]([C:14]([Cl:25])=[O:15])[C:11](=[O:13])[O:12][C:7]=2[C:6]=1[O:19][C:20](=[O:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)c(=O)oc2c1OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)c(=O)oc2c1OC(C)=O

Procedure:
A mixture of 7,8-diacetoxy-2-oxo-2H-1-benzopyran-3-carboxylic acid (612 mg), thionyl chloride (0.5 mL), dimethylformamide (one drop), and benzene (40 mL) was refluxed for 1 hour and then concentrated to about 10 mL. Hexane (20 mL) was added and the separated precipitates were filtered off, followed by vacuum drying, to yield 7,8-diacetoxy-2-oxo-2H-1-benzopyran-3-carbonyl chloride (600 mg).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[O:17])[CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[N:7]([CH3:18])[C:6](=[O:8])[N:5]([CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[O:17])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCC(CC)Cn1c(=O)cc(Cl)[nH]c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCC(CC)Cn1c(=O)cc(Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution containing 20 g of 6-chloro-3-(2-ethylhexyl)uracil thus obtained in 50 ml of dimethylformamide was added 11 g of potassium carbonate and then 12.1 g of methyl iodide was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was poured into water and extracted twice with 100 ml of chloroform. The organic phase was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure to obtain 21 g of 6-chloro-3-(2-ethylhexyl)-1-methyluracil as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC(C[AlH]CC(C)C)C.C(=O)=O.CC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cn1cc(Br)cc(Nc2ccc(CO)cn2)c1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
In a flask under N2, 186a (500 mg, 1.5 mmol) was suspended in methylene chloride and cooled to −78° C. in a dry ice/acetone bath. 1.0M DIBAL-H in methylene chloride (4.4 mL, 4.4 mmol) was slowly added via syringe. After the addition was complete the reaction was allowed to warm to −20° C. at which time the dry ice/acetone bath was exchanged for a ice/water bath and the reaction stirred an additional 0.5 hr at which time it was slowly quenched with 1N HCl (˜5 mL). The reaction was then diluted with ethyl acetate and allowed to stir and warm to room temp over ˜1 hr. The pH was adjusted to ˜7 with 1N NaOH and 50 mL of saturated aqueous Rochelle's salt was added and the mixture heated and stirred at 40° C. for 1 hr during which time the mixture cleared. The layers were separated, the organics washed with brine, dried over Na2SO4, filtered and concentrated to give 186b as a white solid (420 mg, 90% yield).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH2:1]([O:14][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:10]=1[F:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Yield: 102.4 %

Procedure:
Benzyl bromide (2.80 mL, 23.6 mmol) was added to a solution of 2-fluoro-4-bromobenzoic acid (4.34 g, 19.8 mmol) and Cs2CO3 (9.79 g, 30.0 mmol) in CH2Cl2 (50 mL). The mixture was heated to reflux for 4 hr. The reaction was quenched with H2O (150 mL) and extracted with CH2Cl2 (150 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 10% EtOAc in hexanes to give a colorless oil (6.27 g, 100% yield). 1H NMR (400 MHz, CDCl3) δ 7.82-7.88 (m, 1 H) 7.44-7.47 (m, 2 H) 7.34-7.42 (m, 5 H) 5.38 (s, 2 H).
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[CH3:29])[CH3:12].CN(C)CCCN=C=NCC.[CH3:42][C:43]1[N:44]=[C:45]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)[S:46][C:47]=1[C:48](O)=[O:49]>C(OCC)(=O)C.C(OCC)C>[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:48]([C:47]3[S:46][C:45]([C:51]4[CH:52]=[CH:53][C:54]([C:57]([F:60])([F:58])[F:59])=[CH:55][CH:56]=4)=[N:44][C:43]=3[CH3:42])=[O:49])[CH2:24]2)[CH:20]=[CH:19][C:18]=1[CH3:29])[CH3:12]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Reactant: CCOC(=O)COc1cc(C2CCCNC2)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
(2-methyl-5-piperidin-3-yl-phenoxy)-acetic acid ethyl ester L-tartaric acid salt (147 mg, 0.34 mmol) was dissolved in 50 mL ethyl acetate and washed with 50 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 2 mL CH2Cl2 and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (132 mg, 0.69 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (99 mg, 0.34 mmol) were added. The reaction was stirred at ambient temperature under nitrogen for 24 h. The reaction was diluted with 100 mL diethyl ether and washed with water (100 mL), 0.5 N HCl (2×100 mL), saturated aqueous NaHCO3 (2×100 mL), dried over Na2SO4 and concentrated under reduced pressure to yield (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-acetic acid ethyl ester (146 mg, 76%) as a clear oil.
Reaction SMILES: ClC1C=C(OCCCN2CCN(C)CC2)C=CC=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[C:27]([CH3:28])[C:22]=2[N:21]=C1.[Cl:30][C:31]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[CH:36]=[CH:35][C:32]=1[CH:33]=O.CC1C(C)=CC=C(N)C=1N>CN(C=O)C>[Cl:30][C:31]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[CH:36]=[CH:35][C:32]=1[C:33]1[NH:19][C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[C:27]([CH3:28])[C:22]=2[N:21]=1
Reactant: CN1CCN(CCCOc2ccc(C=O)c(Cl)c2)CC1
Reactant: Cc1ccc2c(ncn2-c2ccc(OCCCN3CCN(C)CC3)cc2Cl)c1C
Agent: Cc1ccc(N)c(N)c1C
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c(-c3ccc(OCCCN4CCN(C)CC4)cc3Cl)nc2c1C
Yield: 76 %

Procedure:
2-{(2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole. 2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (91.5 mg, 0.31 mmol, 1.0 equiv) and 3,4-dimethyl-benzene-1,2-diamine (42 mg, 0.31 mmol, 1.0 equiv) were stirred with Na2S2O5 (76 mg, 0.40 mmol, 1.3 equiv) in DMF (0.25 M) at 90° C. for 12 h. The reaction mixture was loaded directly on silica gel and purified according to Method 2, which afforded 98 mg (76%) of the title compound. MS (electrospray): mass calculated for C23H29ClN4O, 412.20; m/z found, 413.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.68 (br s, 1H), 7.33 (br s, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.7, 2.5 Hz, 1H), 7.03 (dd, J=8.7, 2.5 Hz, 1H), 4.13 (t, J=6.1 Hz, 2H), 2.60-2.39 (m, 13H), 2.39 (s, 3H), 2.30 (s, 3H), 2.05-1.95 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C1COCC1.C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][NH:22]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1OCC
Yield: 43 %

Procedure:
To a solution of the product of Step B (0.06 g; 0.172 mmol) in 1M BH3 in THF (0.35 ml; 0.35 mmol) TFA (0.4 ml) was added drop wise at 0° C. with stirring. After the addition was completed (˜5 min), the reaction was quenched with H2O (0.5 ml) and solvents were removed under reduced pressure. The residue was diluted to 10 ml with EtOAc and was washed with 10% NaOH (2×2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.026 g; 43%) as a creamy foam, which was used in the next step without further purification. 1H-NMR (CDCl3) 7.78 (dd, 1H, J=1.9, 7.2 Hz); 7.68 (d, 1H, J=1.9 Hz); 7.52 (d, 1H, J=7.2 Hz); 7.17 (t, 1H, J=7.7); 6.97 (d, 1H, J=8.5 Hz); 6.75 (d, 1H, J=7.7 Hz); 4.19 (m, 4H); 3.65 (t, 2H, J=8.9 Hz); 3.45 (tr, 2H, J=8.9 Hz); 1.7 (broad s, 1H+H2O); 1.49 (m, 6H).