Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCCBr
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: N#CCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A suspension of 4,4-diphenylpiperidine (4.15 g, 17.5 mmol, 1.00 equiv), 4-bromobutyronitrile (2.10 mL, 21.0 mmol, 1.20 equiv, Aldrich), potassium carbonate (4.85 g, 35.0 mmol, 2.00 equiv), and potassium iodide (581 mg, 3.50 mmol, 0.20 equiv) in n-butanol (20 mL) and 1,4-dioxane (20 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. Water (50 mL) was added and the mixture was extracted with CH2Cl2 (4×150 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to afford 4.65 g (87%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:26])[C:11]([CH3:25])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=3[CH3:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:26])[C:11]([CH3:25])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([CH:19]=[CH:20][C:21]=3[CH3:22])[O:23][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(O)c2C)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution 3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-dimethyl-phenol (87.5 mg, 0.25 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (0.16 g, 0.51 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 30 min then isopropyl bromoacetate (56 mg, 0.3 mmol, 1.2 eq) was added and the reaction stirred for a further 1 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 30:1) to give the title compound as a colorless oil (80 mg, 69%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+](C1C=CC([O:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)=O)=CC=1)([O-])=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:16][O:17][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:27])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCOCC1CO
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: -10 °C
Yield: 67.9 %

Procedure:
NaH (60% in oil, prewashed with hexane; 1.30 g, 31.7 mmol) was suspended in anhydrous THF (50 mL) under nitrogen and the reaction mixture was cooled to −10° C. with stirring. A solution of 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 2.30 g, 10.6 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 20 min at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 4.38 g, 12.7 mmol) was added and the reaction mixture was stirred overnight at room temperature. Sat aq NaHCO3 solution (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase extracted with EtOAc. The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with EtOAc/hexane. Impure material was further purified by flash normal phase chromatography using 1% MeOH in DCM to give 3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (3.05 g, 68%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[CH:12]=1.O>CS(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[CH:12]=1
Reactant: COCCCCO
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCCCOc1cc[n+]([O-])c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
6.77 g (0.065 mol) of 4-methoxybutanol was dissolved in 60 ml of dimethyl sulfoxide to obtain a solution. 2.6 g (0.065 mol) of 60% sodium hydride was added to this solution at a room temperature in a nitrogen atmosphere. The obtained mixture was heated to 60° C., stirred for one hour and cooled to a room temperature. A solution of 4.66 g (0.032 mol) of 4-chloro-2-methylpyridine 1-oxide in 20 ml of dimethyl sulfoxide was dropwise added to the resulting mixture. The obtained mixture was stirred at 40° C. for one hour. After the completion of the reaction, 5 ml of water was added to the mixture and the obtained mixture was evaporated to dryness to remove the solvent. 150 ml of water was added to the residue. The obtained mixture was extracted with 200 ml of chloroform four times. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain 5.06 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.7 %

Procedure:
4-Amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (0.8 g) was dissolved in dimethylformamide (10 ml), and benzoic acid (0.25 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.44 g) were added. The mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.2 g of 4-amino-N-(1-(4-benzoylaminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:31]=[N:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1.Cl.[CH3:35][O:36][C:37]1[CH:46]=[C:45]2[C:40]([C:41]([NH:47][CH2:48][C:49](O)=O)=[CH:42][CH:43]=[N:44]2)=[N:39][CH:38]=1.C(N(CC)CC)C.S(O)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>CC#N.C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:49]([CH2:48][NH:47][C:41]3[C:40]4[C:45](=[CH:46][C:37]([O:36][CH3:35])=[CH:38][N:39]=4)[N:44]=[CH:43][CH:42]=3)=[N:33][N:32]=2)[N:31]=1
Reactant: COc1cnc2c(NCC(=O)O)ccnc2c1
Reactant: NNc1ccc(Cl)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
In a 250 mL round bottom flask under N2 were dissolved HATU (1762 mg, 4635 μmol), 1-(6-chloropyridazin-3-yl)hydrazine (536 mg, 3708 mol), 2-(7-methoxy-1,5-naphthyridin-4-ylamino)acetic acid hydrochloride (1.00 g, 3708 μmol) in 25 mL of MeCN then stirred and cooled down at −40° C. then treated with TRIETHYLAMINE (2584 μl, 18540 μmol) and warmed to rt. After 30 min the reaction mixture based on LC-MS was evaporated under reduced pressure and dry under high vacuum. The crude solid was dissolved in 100 mL of i-PrOH then treated with Ts-OH (2821 mg, 14832 μmol) and heated at 80° C. After 3 h the reaction mixture based on LC-MS was diluted with DCM then neutralized with NaOH (1N). The aqueous phase was extracted 3× with DCM with 10% MeOH then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was triturated with hot i-PrOH then cooled down and filtered (662 mg) and the mother liquor was evaporated under reduced pressure and purified by MPLC (ISCO) (210 mg) with DCM:MeOH 100:0 to 90:10 to afforded in combined yields N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (872 mg, 69% yield) as a off-white solid. MS m/z=342.1 [M+1]+. Calc'd for C15H12ClN7O: 341.7.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([C:24]#[N:25])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].BrCC1CC1>C1COCC1>[C:24]([C:22]1([CH2:8][CH:9]2[CH2:11][CH2:10]2)[CH2:23][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])[CH2:21]1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: [Li]CCCC
Agent: BrCC1CC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C#N)(CC2CC2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (3.33 g 4.64 ml; 32.92 mmol) in THF (60 ml) at 0° C. was added n-butyllithium (2.5M in hexanes; 13.17 ml; 32.92 mmol). The solution was stirred for 30 minutes then cooled to −78° C. A solution of 3-cyanoazetidine-1-carboxylic acid tert-butyl ester (5 g; 27.43 mmol) in THF (40 ml) was added and the solution stirred for 1 hour. (Bromomethyl)cyclopropane (4.81 g 3.42 ml; 35.67 mmol) was then added dropwise with stirring and the solution stirred for 30 minutes at −78° C., then allowed to warm to ambient temperature, and stirred for 3 hours. The reaction was cooled in an ice bath and quenched with saturated aqueous ammonium chloride. The solvent was evaporated and the residue was partitioned between EtOAc (300 ml) and water (100 ml). The organic phase was separated, dried over MgSO4, filtered and evaporated to give an orange oil. The crude product was passed through a silica gel plug eluted with 15% EtOAc DCM to give the product as a pale yellow oil. (5.25 g)
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C1(O)C=CC=CC=1.[H-].[Na+].F[C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[C:20]=1[C:21]#[N:22]>O1CCCC1.CS(C)=O>[O:1]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]2[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=2[F:34])[C:20]=1[C:21]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(F)cccc1Nc1c(F)cccc1F
Reactant: [O-]c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Solvent: CS(C)=O
Product: N#Cc1c(Nc2c(F)cccc2F)cccc1Oc1ccccc1
Temperature: 110 °C

Procedure:
Sodium phenoxide was generated by dissolving phenol (0.25 g, 2.7 mmol) in dry tetrahydrofuran (5 mL), and adding sodium hydride (0.065 g, 2.7 mmol). After gas evolution ceased, the solvent was evaporated and 2-fluoro-6-(2,6-difluorophenylamino)benzonitrile (0.335 g, 1.35 mmol) dissolved in dimethyl sulfoxide (5 mL) was added. The mixture was heated to 110° C. while stirring under argon. The solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (5×), brine(1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–40% CH2Cl2 in hexane to give the title compound as a white amorphous solid. mp 150–153° C.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH2:4]([C:8]#[CH:9])[CH2:5][CH2:6][CH3:7]>>[CH2:1]([OH:3])[CH2:2][C:7]#[C:6][CH2:5][CH2:4][CH2:8][CH3:9]
Reactant: C#CCCCC
Reactant: C1CO1
Product: CCCCC#CCCO

Procedure:
Into the solution of the Grignard reagent obtained above and kept at 0° to 60° C., ethylene oxide is added dropwise preferably in an amount of 1.6 to 3 times by moles based on the starting butylacetylene and the reaction mixture is hydrolyzed by contacting with an aqueous acidic solution followed by distillation to give 3-octyn-1-ol (reaction (ii)). The yield is usually 80 to 85% of the theoretical value.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2n1
Reaction time: 0.08 h
Yield: 67.5 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (149 mg, 0.664 mmol) in dichloromethane (4 mL) was added pyridine (130 μL, 1.58 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylquinoline (100 mg, 0.632 mmol) was added. The resulting mixture was stirred for 90 min at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (148 mg, 68%), single spot at Rf 0.64 (ethyl acetate). mp 178.1-178.4° C., HPLC purity 99+% (tR 2.27 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.93-7.89 (3H, m), 7.53 (1H, d, J=8.2 Hz), 7.44 (1H, d, J=2.5 Hz), 7.31-7.24 (2H, m), 7.18 (1H, t, J=8.1 Hz), 2.73 (3H, s), 2.69 (3H, s). LCMS: 345.17 (M−). FAB-MS (MH+, C17H15CIN2O2S): calcd 347.0621, found 347.0622.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([CH:7]1[CH:12]([CH3:13])[CH2:11][C:10]([OH:19])([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:9][CH:8]1[CH3:20])=[O:6])[CH3:3].C1C(=O)N([Br:28])C(=O)C1.S([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CN(C=O)C.O>[CH3:3][CH:2]([O:4][C:5]([CH:7]1[CH:8]([CH3:20])[CH2:9][C:10]([C:14]2[S:15][C:16]([Br:28])=[CH:17][N:18]=2)([OH:19])[CH2:11][CH:12]1[CH3:13])=[O:6])[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)OC(=O)C1C(C)CC(O)(c2nccs2)CC1C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)OC(=O)C1C(C)CC(O)(c2ncc(Br)s2)CC1C
Temperature: 55 °C
Yield: 58.7 %

Procedure:
To a solution of the product of Step 2 (1.4 g, 4.7 mmol) in DMF (15 mL) was added NBS (0.963 g, 5.41 mmol) and the resulting solution heated to 55° C. After 60 min the reaction was cooled and a solution of sodium sulfite (500 mg) in water (30 mL) was added followed by EtOAc. The layers were separated, the aqueous layer was back extracted twice with EtOAc and the combined organics were dried with MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography to afford propan-2-yl-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,6 dimethylcyclohexanecarboxylate (1.04 g, 2.76 mmol) MS ESI: [M+H]+ m/z 375.9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH:6]=[N:5]2.[C:21]([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O1CCOCC1.C(OCC)(=O)C>[C:24]([O:23][C:21]([N:28]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH:6]=[N:5]3)[CH:30]=[N:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: C[C@@H](Nc1cnc2cc(Br)ccc2n1)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](Nc1cnc2cc(-c3cnn(C(=O)OC(C)(C)C)c3)ccc2n1)c1ccccc1
Temperature: 108 °C

Procedure:
A mixture of (6-Bromo-quinoxalin-2-yl)-((R)-1-phenyl-ethyl)-amine (0.42 g, 1 eq, 1.28 mmol), 1-boc-4-pyrazole boronic acid pinacol ester (0.45 g, 1.2 eq, 1.53 mmol), caesium carbonate (1.66 g, 4.0 eq, 5.1 mmol) and potassium iodide (0.021 g, 0.1 eq, 0.13 mmol) in 1,4-dioxane (20 mL) was degassed at RT under vacuum and then placed under an atmosphere of nitrogen. The process was repeated twice and Fu's catalyst (Bis(tri-tert-butylphosphine)palladium(0)) (0.033 g, 0.05 eq, 0.06 mmol) was added at room temperature. The reaction mixture was heated at 108° C. in a microwave reactor for 180 minutes. After completion of the reaction (confirmed by TLC), the reaction mixture was diluted with ethyl acetate (200 mL) and then washed with water (50 mL×3) and brine (50 mL). The organic layer was dried and concentrated to give the crude product.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][S:11][C:5]2=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1OS(C(F)(F)F)(=O)=O.[F:23][C:24]1[CH:29]=[C:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[CH:26][C:25]=1[NH2:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:23][C:24]1[CH:29]=[C:28]([Si:30]([CH3:32])([CH3:31])[CH3:33])[CH:27]=[CH:26][C:25]=1[NH:34][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]2[S:11][CH2:10][CH2:9][N:6]2[C:7](=[O:8])[C:2]=1[CH3:1]
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2n(c1=O)CCS2
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(Nc2ccc([Si](C)(C)C)cc2F)c([N+](=O)[O-])c2n(c1=O)CCS2
Yield: 76.2 %

Procedure:
Trifluoro-methanesulfonic acid 6-methyl-8-nitro-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-7-yl ester (0.9 g, 2.5 mmol) was reacted with 2-fluoro-4-trimethylsilanyl-phenylamine (0.5 g, 2.75 mmol), Pd(dba)3 (138 mg, 0.15 mmol), potassium phosphate (0.7 g, 3.75 mmol) and xantphos (87 mg, 0.15 mmol) in toluene (30 mL) at 110° C. for 3 hours to afford the crude product. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 0.75 g of the product (76% yield).
Reaction SMILES: B.[OH2:2].[OH-].[Na+].OO.[CH2:7]([C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:11]=1[O:12][Si](C)(C)C)[CH:8]=[CH2:9]>O1CCCC1>[OH:2][CH2:9][CH2:8][CH2:7][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:11]=1[OH:12]
Reactant: O
Reactant: C=CCc1cccc(C)c1O[Si](C)(C)C
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CCCO)c1O
Reaction time: 1 h

Procedure:
In dry tetrahydrofuran (abbreviated as THF) was dissolved 42.7 parts of the above-obtained 2-allyl-6 -methylphenoxytrimethylsilane in a nitrogen atmosphere. Thereto was added dropwise at 5° C. 86.2 parts of a 1 mol/l THF solution of a borane, and this mixture was allowed to react at 20° C. for 1 hour. To the resulting reaction mixture was added 15 parts of pure water, followed by 45 parts of 10% aqueous sodium hydroxide solution. Subsequently, 40 parts of 30% hydrogen peroxide was added dropwise to the reaction mixture at 40° C. and reaction was further conducted at 50° C. for 1 hour. Through extraction with diethyl ether, the desired compound, 2-(3 hydroxypropyl)-6-methylphenol, was obtained from the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1>>[N:33]1[CH:34]=[CH:35][C:30]([NH:29][C:13]([C:12]2[S:11][C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:15])=[N:31][CH:32]=1
Reactant: Nc1ccncn1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)Nc4ccncn4)s3)c2cc1OC
Yield: 69.6 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and 4-aminopyrimidine (9.5 mg, 0.1 mmol, Aldrich) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid pyrimidin-4-ylamide (34.3 mg, 69.7%) as a white solid. MS m/z 493 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:21][CH:22]([CH2:26][CH2:27][CH3:28])[C:23](O)=[O:24])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([C:8]1[NH:13][C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:11][N:10]2[C:23](=[O:24])[C:22]([CH2:26][CH2:27][CH3:28])=[N:21][C:9]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc2c(Cc3ccccc3)[nH]c(-c3ccc(O)cc3)cn-2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
2-((3-benzyl-5-(4-hydroxyphenyl)pyrazin-2-yl)amino)pentanoic acid (49 mg, 0.13 mmol) was dissolved in DCM (10 mL). Pyridine (0.5 mL) was added followed by N,N′-Dicyclohexylcarbodiimide (54 mg, 0.26 mmol). The reaction mixture was slowly stirred at room temperature for 1 hr. The solvent was evaporated, and the residue purified by flash chromatography (eluting solvent: EtOAc to DCM to 10% methanol in DCM) to give the product as a yellow powder (40 mg, 86%). NMR (300 MHz, CD3OD, δ): 7.35 (m, 8H), 6.88 (d, J=9.0 Hz, 2H), 4.40 (s, 2H), 2.81 (t, J=7.5 Hz, 2H), 1.81 (m, 2H), 1.02 (t, J=7.5 Hz, 3H); MS (ESI) m/z 359.0.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>CS(C)=O>[CH3:22][O:21][C:19]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:23]([O-:25])=[O:24])[C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:20]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1C(C(=O)OC)C(=O)OC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Dimethyl malonate (6.0 mL) was added to an ice-cold suspension of 2.1 g of sodium hydride in 15 mL of DMSO. The reaction mixture was then stirred at 100° C. for 1.0 h and then cooled to room temperature. 2-Chloro-3-methoxycarbonyl-nitrobenzene (2.15 g) was added to the above mixture in one portion and the mixture was heated to 100° C. for 1.5 h. The reaction mixture was then cooled to room temperature and poured into ice water, acidified to pH 5, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3.0 g of the dimethyl 2-methoxycarbonyl-6-nitrophenylmalonate.