Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH:41]=1)OC1C=CC=CC=1)#[N:25]>>[C:24]([NH:26][C:27]([NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:21])=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]2)[CH:41]=1)#[N:25]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.63 g (2.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=615 ([M+H]+, 14), 229 (100), 109 (96); IR (KBr): 2167 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 65°-68° C. (ethanol/ether).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[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.[CH2:23]([NH:30][CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:23]([N:30]([CH3:31])[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[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)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNCc1ccccc1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)Cc3ccccc3)nc2c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.63 mmol) in DMSO (4 mL) was added benzyl(methyl)amine (92 mg, 0.76 mmol), and DIEA (163 mg, 1.26 mmol). The resulting solution was stirred for 2 hours at 85° C. Then the mixture was quenched of water (100 mL) and extracted with dichloromethane (3×50 mL) The organic layers were combined and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[benzyl(methyl)amino]-2-(4-fluorophenyl)quinoxaline-6-carboxylate as yellow oil (100 mg, 39%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:10]1[N:18]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1NC1CCOCC1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1C1CCOCC1
Temperature: 70 °C
Yield: 77.5 %

Procedure:
{(S)-1-[2-(Tetrahydropyran-4-ylamino)phenylcarbamoyl]ethyl}carbamic acid tertbutyl ester (1.90 g, 5.23 mmol) was dissolved in AcOH (30 mL) and heated to 70° C. for 18 h. Volatiles were then removed in vacuo and the residue was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×2) and the combined organic layers were then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-4% 2M NH3/MeOH in DCM) affording {(S)-1-[1-(Tetrahydropyran-4-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tertbutyl ester as a white foam (1.40 g, 77%). LCMS: RT 2.23 min [M+H-tBu]+ 290.1.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])=[CH:9][CH:8]=1)=[O:6].Br[CH2:29][CH2:30][C:31]1([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:32]1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][C:31]1([CH2:30][CH2:29][C:15]([CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:12][CH:11]=2)([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH2:32][CH2:33]1)[CH3:39]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Reactant: CCOC(=O)CC1(CCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(CCC1(CC(=O)OCC)CC1)C(=O)OCC=C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Under argon and at 0° C., 0.22 g (5.41 mmol) of sodium hydride (60% strength dispersion in mineral oil) is added a little at a time to a solution of 1.34 g (3.87 mmol) of diallyl 2-[4-(methoxy-carbonyl)phenyl]ethylmalonate in 10 ml of anhydrous DMF. The mixture is stirred at 40° C. for 30 min, and a solution of 1.00 g (4.25 mmol) of ethyl [1-(2-bromoethyl)cyclopropyl]acetate in 5 ml of anhydrous DMF is then added dropwise at this temperature. The reaction mixture is then heated at 110° C. for 12 hours. After addition of 100 ml of water and 100 ml of ethyl acetate and phase separation, the aqueous phase is extracted with ethyl acetate. The organic phase is then washed five times with water and once with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The crude product is purified by preparative HPLC. This gives 0.33 g (17% of theory) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>O1CCCC1>[CH2:23]([O:22][CH2:21][C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCOCc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(COCc1ccccc1)(C(=O)OCC)C1CCCCC1
Reaction time: 1 h
Yield: 107.2 %

Procedure:
Diethyl cyclohexylmalonate (18.7 g.) was added to a stirred suspension of sodium hydride (4.8 g. 50% dispersion in oil) in dry tetrahydrofuran (50 ml) under nitrogen. The mixture was refluxed, with stirring, for one hour. The mixture was cooled and benzyl chloromethyl ether (13.9 g.) in dry tetrahydrafuran (50 ml) was added and the mixture was refluxed, with stirring, for three hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. Diethyl 2-benzyloxymethyl-2-cyclohexyl-malonate (30 g.) was obtained as a brown oil and was used without further purification.
Reaction SMILES: OCC=C(CCC=C(CCC=C(C)C)C)C.N1C=CN=C1.CN(C)C=O.[Si:27]([Cl:44])([C:40]([CH3:43])([CH3:42])[CH3:41])(C1C=CC=CC=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:40]([SiH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[Cl:44])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[SiH](Cl)c1ccccc1
Yield: 99 %

Procedure:
Synthesis was carried out with farnesol as a starting material. A protective group was bonded to the hydroxy group of farnesol using imidazole, anhydrous dimethylformamide, anhydrous dichloromethane, and tert-butyldiphenylsilyl chloride (TBDPS) to obtain a TBDPS-protected form (compound represented by (di) below) (yield: 99%). Next, this compound was reacted with m-chloroperbenzoic acid in an anhydrous dichloromethane solvent to obtain an epoxy form (compound represented by (dii) (below) (yield: 29%). Next, the epoxy was subjected to periodic acid oxidation using orthoperiodic acid in a mixed solvent of ether and tetrahydrofuran to obtain an aldehyde form (compound represented by (diii) below) (yield: 73%). A Grignard reagent was prepared from ethyl iodide and magnesium in an anhydrous ether solvent and then reacted with the aldehyde to form an alcohol form (compound represented by (div) below) (yield: 80%). The secondary hydroxy group of the racemic alcohol form and (S)-MaNP acid were subjected to reaction in the presence of N,N-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, and (+)-10-camphorsulfonic acid in an anhydrous dichloromethane solvent to obtain diastereomers. Then, the diastereomers were optically resolved by HPLC, and the absolute configuration was determined by NMR to optically obtain a compound represented by (dv) below (yield: 80%). The TBDPS protective group was then deprotected using tetra-n-butylammonium hydrate in anhydrous tetrahydrofuran to obtain a diol form (compound represented by (dvi) below) (yield: 80%). Next, the primary hydroxy group was replaced by chlorine using N-chlorosuccinimide and dimethyl sulfide in an anhydrous dichloromethane solvent at −40° C. or lower to obtain a chloride (compound represented by (dvii) below) (yield: 80%). Next, the chloride was diphosphorylated using tris-tetra-n-butylammonium hydrogen pyrophosphate in anhydrous acetonitrile to obtain a compound represented by (dviii) below (compound represented by the formula (D)) as the substance of interest (yield: 46%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:27])[NH:5]1.I[C:37]1[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([C:37]3[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=3)=[CH:16][CH:17]=2)[CH3:11])[C:6](=[O:27])[NH:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Reactant: Cn1ccc(I)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Yield: 54.4 %

Procedure:
To a solution of (S)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)tetrahydropyrimidin-2(1H)-one (170 mg, 0.36 mmol) and 4-iodo-1-methylpyridin-2(1H)-one (100 mg, 0.43 mmol) in dry 1,4-dioxane (5 mL) was added 2M aq Cs2CO3 (1 mL) and Pd(PPh3)Cl2 (21.4 mg, 0.03 mmol). After addition, the mixture was heated to reflux for 2 h under N2 atmosphere. The solid was filtered off and diluted with water (30 mL) and EtOAc (30 mL). The mixture was extracted with EtOAc (3×40 mL), and the combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep TLC to afford (S)-4-(2-hydroxy-2-methylpropyl)-1-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-4-phenyltetrahydropyrimidin-2(1H)-one (90 mg, yield: 54.4%). 1H NMR (CDCl3): 0.661 (s, 3H), 1.23 (s, 3H), 1.49-1.50 (m, 3H), 1.98-2.02 (m, 2H), 2.05-2.13 (m, 1H), 2.17-2.18 (m, 2H), 2.60-2.63 (m, 1H), 2.74-2.78 (m, 1H), 3.57 (s, 3H), 5.87-5.92 (m, 1H), 6.35-6.37 (m, 1H), 6.71-6.72 (d, 1H), 7.18-7.22 (m, 2H), 7.23-7.25 (m, 1H), 7.30-7.32 (m, 2H), 7.33-7.37 (m, 5H).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.O.[CH3:20]O>>[CH3:20][O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=1
Reactant: O=C(O)CCCCc1ccc(F)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)CCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Thionylchloride (288 μl, 3.98 mmol) was added dropwise to a solution of 5-(4-fluoro-phenyl)-pentanoic acid (520 mg, 2.65 mmol) in methanol (11 ml) at −15° C. The reaction mixture was then stirred at room temperature for 1.5 h. Water was added and the mixture was extracted 3 times with diethylether. The combined extracts were washed with water and brine, dried (Na2SO4) and evaporated. The remaining residue was purified by column chromatography (silica gel, ethyl acetate/heptane 5:95 to 12:88) to obtain 5-(4-fluoro-phenyl)-pentanoic acid methyl ester (420 mg, 2 mmol; 75%) as colorless liquid. MS: m/e 211.0 [M+H+].
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C:14]([CH3:25])([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](Cl)=[O:16].C(O)(=O)C>O1CCCC1.CCCCCC>[CH3:13][C:14]([CH3:25])([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)(C)Cc1ccccc1)OC
Reaction time: 2 h

Procedure:
To a solution of dimethyl methylphosphonate (63 g.) in tetrahydrofuran (600 ml.) under nitrogen at -75°, there is added 312 ml. of 1.6 M n-butyl lithium in hexane, while maintaining the temperature below -55°. A solution of 2,2-dimethyl-3-phenylpropionyl chloride (part 2, 48.2 g.) in tetrahydrofuran is added while maintaining the temperature below -60°. The mixture is stirred at that temperature for 2 hrs. and then the temperature is allowed to rise to about 25° C. and the mixture is stirred at that temperature for 16 hrs. Acetic acid (20 ml.) is added, the mixture is concentrated, the residue is shaken with a mixture of diethyl ether-methylene chloride (3:1, v/v) and cold dilute sodium bicarbonate solution. The organic layer is separated, washed with brine, dried and concentrated. The residue is crystallized from diethylether to give the title compound, 62 g.; m.p. 48°-51°; NMR peaks at 7.2, 3.83 and 3.64, 3.28 and 2.9, 2.8 and 1.13 δ.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[CH2:5])[CH2:3][CH2:2]1.CC(C)C(BC(C(C)C)C)C.[OH-].[Na+].OO.C(=O)([O-])[O-:29].[K+].[K+]>O1CCCC1.CO>[CH:1]1([CH:4]([C:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=2)[CH2:5][OH:29])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: C=C(c1ccc(Cl)cc1)C1CC1
Agent: CC(C)C(C)BC(C)C(C)C
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: OCC(c1ccc(Cl)cc1)C1CC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 3.5 grams (0.019 mole) of 1-cyclopropyl-1-(4-chlorophenyl)ethene in 10 mL of distilled tetrahydrofuran was cooled to 0° C., and 29.5 mL (0.020 mole) of 0.68S M bis(3-methyl-2-butyl)borane in tetrahydrofuran was added via syringe during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at 0° C. for 1.3 hours, at ambient temperature for 2.5 hours, and at 60° C. for 0.75 hour. The reaction mixture was cooled to 0° C., and 17 mL of methanol, 8.8 mL of aqueous 10% sodium hydroxide solution, and 8.0 mL of aqueous 30% hydrogen peroxide solution were sequentially added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was heated at 60° C. for 30 minutes and then was cooled, after which 30 mL of an aqueous solution saturated with potassium carbonate was added. The aqueous layer was separated and extracted with three 30 mL portions of diethyl ether. The organic materials were combined and washed with 30 mL of an aqueous, saturated potassium carbonate solution. The organic layer was dried with magnesium sulfate/potassium carbonate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.8 grams of 2-cyclopropyl- 2-(4-chlorophenyl)ethanol. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[Se](=O)=[O:15]>>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=[C:2]([CH:1]=[O:15])[CH:11]=1
Reactant: Cc1ccc2nc(C)cc(C)c2c1
Reactant: O=[Se]=O
Product: Cc1ccc2nc(C=O)cc(C)c2c1
Yield: 61 %

Procedure:
The title compound was prepared from 2,4,6-trimethylquinoline (6a) and selenium dioxide using methods as described in the literature for similar compounds (Mathes et al., 1957) in 61% yield. 1H NMR (DMSO-d6, HMDSO), δ: 2.58 (3H, s); 2.72 (3H, s); 7.72 (1H, dd, J=1.8 Hz and J=8.6 Hz); 7.76 (1H, s); 7.92 (1H, unresolved d); 8.09 (1H, d, J=8.6 Hz), 10.05 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1cccs1
Reactant: FC(F)(F)c1cccc(Br)c1
Product: FC(F)(F)c1cccc(-c2cccs2)c1

Procedure:
3-Bromobenzotrifluoride and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20-(1) to give 2-(3-trifluoromethylphenyl)thiophene as colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:15]=[CH2:16])=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:30]=[C:29](I)[CH:28]=[CH:27][C:26]=1[N:32]1[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:34](=[O:45])[CH2:33]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:17]([O:24][C:25]1[CH:30]=[C:29](/[CH:16]=[CH:15]/[C:14]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:11]=[CH:12][CH:13]=2)[CH:28]=[CH:27][C:26]=1[N:32]1[S:36](=[O:37])(=[O:38])[N:35]([CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[C:34](=[O:45])[CH2:33]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=Cc1ccnn1COCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/c3ccnn3COCc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 110 °C

Procedure:
A mixture of 1-benzyloxymethyl-5-vinyl-1H-pyrazole (385 mg, 1.80 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (500 mg, 0.90 mmol), Pd(OAc)2 (13 mg, 0.06 mmol), P(o-tolyl)3 (43 mg, 0.14 mmol) and triethylamine (0.21 mL, 1.5 mmol) in MeCN is heated at 110° C. for 30 min in a microwave apparatus. The reaction mixture is concentrated and chromatographed using a gradient of 15-30% EtOAc/hexanes to afford the title compound as a yellow oil: (M+1)+=631.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC([N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=O)(C)(C)C>C1COCC1>[C:1]([C:5]1[O:6][C:7]2[C:13]([S:14]([N:33]3[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)N3CCCNCC3)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (5.54, 18 mmol) and triethylamine (2.51 mL, 18 mmol) in THF (100 mL) at 0° C. was added homopiperazine-carboxylic acid tert-butyl ester (3.0 g, 15 mmol). The reaction was warmed to room temperature and allowed to stir overnight. The solution was concentrated and then diluted with water and extacted with ethyl acetate (3 times). The combined organic layers were dried with MgSO4, filtered, and concentrated. Flash chromatography (80% ethyl acetate/20% Ethanol) on silica gel gave the title compound (4.0 g, 61%). LC-MS m/z 473.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][N:23]=4)[N:18]=[CH:17][C:16]=3[N+:25]([O-])=O)[O:10][N:9]=2)=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][N:23]=4)[N:18]=[CH:17][C:16]=3[NH2:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Solvent: CO
Product: Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Yield: 60.2 %

Procedure:
A solution of N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitro[1,5]naphthyridin-4-amine (15.02 g, 41.11 mmol) in hot methanol (4 L) was filtered to remove a solid and then added to a Parr vessel charged with 5% platinum on carbon (1.5 g) that had been purged with nitrogen and wet with methanol (50 mL). The vessel was purged with hydrogen three times and then placed under hydrogen pressure (25 psi, 1.7×105 Pa) for 12 hours. The catalyst was removed by filtration and washed with a mixture of dichloromethane and methanol, and the filtrate was concentrated under reduced pressure to provide 8.3 g of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}[1,5]naphthyridine-3,4-diamine containing an impurity.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH:31]1([C:37](O)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:25][C:18]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([NH:1][C:37]([CH:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:38])=[CH:3][C:4]([C:27]([F:30])([F:29])[F:28])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:26])[CH2:13]2)=[N:22][CH:21]=[C:20]([CH2:23][OH:24])[CH:19]=1
Reactant: O=C(O)C1CCCCC1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(N)c2[nH]1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)C3CCCCC3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Amino-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol from (221 mg, 0.5 mmol, Example 175b) and cyclohexanecarboxylic acid (71 mg, 0.55 mmol, Aldrich) reacted under the conditions of Example 65 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 551 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[SH:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: CCOC(=O)CCS
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCSc1cccc(Br)c1
Temperature: 60 °C

Procedure:
A mixture of 1-bromo-3-iodobenzene (3 g) and 1,1′-bis(diphenylphosphino)ferrocene (90 mg) in dimethylformamide (10 ml) and triethylamine (2 ml) was treated with tris(dibenzylideneacetone)dipalladium (175 mg) at 20° C. under nitrogen. After 10 min ethyl 3-mercaptopropionate (1.14 ml) was added and the mixture was heated to 60° C. for 1.5 h. The mixture was diluted with ethyl acetate and washed with 2M hydrochloric acid, brine and dried (MgSO4). The filtrate was concentrated and chromatographed on a biotage cartridge (40 g) eluting with dichloromethane-cyclohexane (1:3) to give the title compound (1.58 g) LCMS RT=3.50 min