Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.[C:11](#[N:14])[CH:12]=[CH2:13].C1N2CCN(CC2)C1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[C:12]([C:11]#[N:14])[CH2:13][O:10]2)=[CH:8][CH:9]=1
Reactant: C=CC#N
Reactant: O=Cc1ccc(Br)cc1O
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Product: N#CC1=Cc2ccc(Br)cc2OC1

Procedure:
A mixture of 4-bromo-2-hydroxybenzaldehyde (20 g), acrylonitrile (26.4 g) and DABCO (0.78 g) was heated at reflux for 8 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was concentrated and the residue was filtered through silica gel. The 7-bromo-2H-chromene-3-carbonitrile thus obtained (7.5 g) was boiled at reflux with sodium hydroxide solution (10.2 g of sodium hydroxide in 100 ml of water) for 8 hours. The cooled reaction mixture was washed with methyl tert-butyl ether, acidified with hydrochloric acid and extracted with ethyl acetate. Concentration of the organic phase gave 7-bromo-2H-chromene-3-carboxylic acid. This acid (3.0 g) was heated to 85° C. with DPPA (3.2 g), triethylamine (1.6 ml) and toluene (30 ml) for 12 hours. Then hydrochloric acid (6 N) was added and the mixture was heated to reflux for 2 hours. The cooled reaction mixture was extracted with ethyl acetate and the organic phase was concentrated. The product was thus obtained with the molecular weight of 227.06 (C9H7BrO2); MS (ESI): 227 (M+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].Cl.[CH2:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][C:8]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:9]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc(Cc2cccnc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCl)c1ccc(Cc2cccnc2)cc1
Yield: 86.6 %

Procedure:
In 15 ml of methylene chloride was suspended 8.1 g of anhydrous aluminum chloride, and 3.0 ml of 3-chloropropionyl chloride was added to the suspension with ice-cooling, after which 5.0 g of 3-benzylpyridine hydrochloride was added in small portions to the resulting mixture over 30 minutes. The resulting mixture was subjected to reaction at room temperature for one hour, and then the reaction mixture was added to 30 ml of iced water. The crystals thus precipitated were collected by filtration, and suspended in a mixture of 50 ml of ethyl acetate and 30 ml of water, after which the resulting suspension was neutralized with sodium hydrogen-carbonate with ice-cooling. Insolubles were removed by filtration, and the organic layer of the filtrate was separated, washed with 10 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 5.5 g (yield 86.6%) of pale yellow, oily 3-[p-(3-chloropropionyl)benzyl]pyridine.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][N:6]=[C:7]([CH3:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:17][NH2:18]>>[CH3:15][C:7](=[N:6][O:5][CH2:4][C:3]([NH:18][CH3:17])=[O:2])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: COC(=O)CON=C(C)c1ccc(Cl)cc1
Reactant: CN
Product: CNC(=O)CON=C(C)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 5.0 g of the [(α-methyl-4-chlorobenzylidene amino)oxy] acetic acid methyl ester obtained by the method described in example 3 and 40 ml of 35% aqueous methylamine solution was stirred for 2 hours. The precipitated solid substance was then dissolved by thrice extracting the mixture with an ether chloroform mixture. The extract was washed thrice with water, dried over anhydrous sodium sulfate and then concentrated by evaporation. Crystallisation of the residue from a benzene petroleum ether mixture yielded the above substance. Melting point 115° C.-116° C.
Reaction SMILES: [CH:1]([C:9]1=[CH:10][C:11]([O:13][C:14]1=[O:15])=O)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=CC1C=CC=CC=1.C1C(=O)OC(=O)C=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>CN(C)C=O>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][N:36]1[C:14](=[O:15])[CH:9]=[CH:10][C:11]1=[O:13]
Reactant: CN(C)CCCN
Reactant: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Agent: O=C1C=CC(=O)O1
Solvent: C=Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)CCCN1C(=O)C=CC1=O
Temperature: 110 °C

Procedure:
A solution of 250 g of copoly(styrene-maleic anhydride (commercially available from the Monsanto Chemical Company under the tradename of Lytron 810) in 2500 ml of dry dimethylformamide is made by stirring in a 5-liter flask, containing a reflux condenser, thermometer, stirrer, and dropping funnel. The mixture is heated to 110°C and 230 g of N,N-dimethyl-1,3-propanediamine is added slowly at a rate to keep the mixture boiling slightly. Polymer precipitates as a gummy mass at first but goes back into solution after about half of the amine is added. The condenser is replaced by a distillation column and about 500 ml of material is removed by distillation with stirring. The residue is cooled, precipitated in water, collected by filtration and air-dried at room temperature for 2 days. The solid is dissolved in acetone, and again precipitated in water and air-dried. Yield = 260 g of off-white, friable solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:22])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:7]1[CH:23]=[CH:24][CH:25]=[CH:26][C:6]=1[N:5]2[CH3:27].[CH:28]1([CH2:31][O:32][C:33]2[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[CH:37][C:34]=2[CH:35]=O)[CH2:30][CH2:29]1.[O-]CC.[Na+]>C(O)C>[CH:28]1([CH2:31][O:32][C:33]2[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[CH:37][C:34]=2/[CH:35]=[CH:1]/[C:2]2[N:3]=[C:4]3[N:8]([C:9](=[O:22])[C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]=2[N:5]3[CH3:27])[CH2:29][CH2:30]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1nc2n(C)c3ccccc3n2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3n(C)c4ccccc4n3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CC1
Yield: 92.5 %

Procedure:
The title compound was synthesized by condensation of Intermediate 25 (300 mg, 0.801 mmol) with 2-cyclopropylmethoxy-3-methoxy benzaldehyde (215 mg, 1.010 mmol) in presence of sodium ethoxide (108 mg, 1.610 mmol) in ethanol (25 ml) according to the procedure described in Example 24 to afford crude product which was purified by column chromatography to give 416 mg of the desired compound; 1H NMR (300 MHz, DMSO-d6) δ 0.23-0.32 (m, 2H), 0.49-0.56 (m, 2H), 1.12 (br s, 1H), 3.70-3.78 (m, 6H), 3.87 (s, 2H), 6.91-6.99 (m, 3H), 7.20-7.26 (m, 1H), 7.32-7.38 (m, 1H), 7.45-7.54 (m, 5H), 7.68 (d, J=8.4 Hz, 1H), 8.27 (d, J=16.2 Hz, 1H), 8.37-8.43 (m, 1H); APCI-MS (m/z) 562.49 (M+H)+.
Reaction SMILES: Br[CH:2]([CH:8](Br)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.COC1C=C(C(=O)C#CC(OC)=O)C=CC=1OC>C(Cl)Cl>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:9](=[O:10])[C:8]#[C:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: CCOC(=O)C(Br)C(Br)C(=O)c1ccc(OC)c(OC)c1
Agent: COC(=O)C#CC(=O)c1ccc(OC)c(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C#CC(=O)c1ccc(OC)c(OC)c1
Yield: 81.7 %

Procedure:
A solution of ethyl 2,3-dibromo-4-(3,4-dimethoxyphenyl)-4-oxobutanoate (4.76 g, 11.2 mmol), prepared above, in methylene chloride (20 ml) and a solution of triethylamine (4 g) in methylene chloride (5 ml) were subjected to reaction and treatment in the same manner as described above in connection with Intermediate 1. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate) to give the title compound (2.4 g, 82%) as a yellow crystal.
Reaction SMILES: [CH:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]3([CH3:30])[CH2:28][O:27][C:26](=[O:29])[NH:25]3)[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[I:34]N1C(=O)CCC1=O>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[C:15]([I:34])=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]3([CH3:30])[CH2:28][O:27][C:26](=[O:29])[NH:25]3)[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@@H](C5CCCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@]1(c2ccc3c(I)c(O[C@H]4CC[C@@H](C5CCCCC5)CC4)ccc3c2)COC(=O)N1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 92312.5 %

Procedure:
To a solution of (R)-4-(6-(cis-4-cyclohexylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (35.0 mg, 0.0000859 mol) in methylene chloride (2 mL, 0.03 mol), N-iodosuccinimide (38.6 mg, 0.000172 mol) was added, followed by zirconium tetrachloride (4.00 mg, 0.0000172 mol) at 23° C. The reaction mixture was then sonicated and stirred for 5 minutes at 23° C. TLC and LC/MS indicated a clean reaction. The majority of solvent was removed. Solid was removed via filtration through a Celite pad. The mixture was then loaded onto a column (SiO2, 4 g, 0-50% ethyl acetate/hexanes) to give a pure product (42.3 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[C:4]([F:29])[CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[N:18]([CH3:27])[C:17]2=[O:28])=[C:4]([F:29])[CH:3]=1
Reactant: [H][H]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Yield: 58.9 %

Procedure:
A mixture of 1.12 g (2.61 mmol) of 3-[4-chloro-2-fluoro-5-(phenylmethoxy)phenyl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione and 220 mg of 10% palladium on charcoal in 40 mL of ethyl acetate was placed in a Paar bottle and was agitated under 45 psi hydrogen over a 20 hour period. It was filtered and washed with 100 mL of ethyl acetate. The filtrate was concentrated in vacuo and the resultant crude product flash chromatographed over silica gel eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 521 mg of the title compound as a white foam.: 1H-NMR (CDCl3, 200 MHz) ppm 7.15 (d, 1H) , 6.9 (d, 1H) , 6.4 (s, 1H), 5.8 (s, 1H), 3.6 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:14])[C:11]([OH:13])=O)=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>O1CCCC1>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:11](=[O:13])[C:10](=[N:9][NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH3:14])=[CH:31][CH:30]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(=NNc1ccc(Cl)cc1)C(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)C(C)=NNc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-Chlorophenyl hydrazono) propionic acid (0.64 g, 3.0 mmol) was dissolved in tetrahydrofuran (3 ml), and carbonyl diimidazole (0.49 g, 3.0 mmol) was added under cooling with ice. After stirring at room temperature for 1 hour, a solution of 4-methoxybenzyl amine (0.41 g, 3.0 mmol) in tetrahydrofuran (3 ml) was added thereto. 15 hours later, the mixture was washed with 6N hydrocloric acid, 1N aqueous solution of sodium hydroxide and a saturated brine, dried on sodium sulfate and then filtered. The residue obtained by concentrating the resulting filtrate was suspended in a mixed solvent of hexane and chloroform (1:1) and filtered to obtain N-(4-methoxybenzyl)-2-(4-chlorophenyl hydrazono) propionic acid amide (Compound No. 93) (0.76 g, 2.3 mmol, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[O:19][C:6]([C:5]3[CH:20]=[CH:21][C:2]([NH2:1])=[C:3]([N+:22]([O-:24])=[O:23])[CH:4]=3)=[N:8][N:9]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)NNC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COc1ccc(-c2nnc(-c3ccc(N)c([N+](=O)[O-])c3)o2)cc1

Procedure:
A solution of 4-methoxybenzoic acid N′-(4-amino-3-nitrobenzoyl)-hydrazide (750 mg, 2.27 mmol) and Burgess reagent (1.62 g, 6.81 mmol) in THF (15 mL) was microwaved at 150° C. for 20 min. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (heptane/EtOAc=1:3) to give the title compound as a yellow solid. MS: m/z 313 (M+1).
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NC(C)C)(C)C.[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([N:10]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[CH2:9])[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C[C@H](NC1CCCC1)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: C=C[C@@H](c1ccccc1)N(Cc1ccccc1)C1CCCC1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of N-[(1S)-1-phenylprop-2-en-1-yl]cyclopentanamine (24 mg) and diisopropylamine (18 mg) in DCM (2.5 ml) at RT under N2 was added benzoyl chloride (20 mg). This mixture was stirred for 1 h. The reaction was evaporated and purified by flash chromatography (2% EtOAc/hexane) to afford the title compound (15 mg, 44%) as a pale oil. 1H NMR (300 MHz, CDCl3) δ 1.22-2.27 (m, 8H), 3.57 (bs, 1H), 5.28-5.60 (m, 3H), 6.23 (bs, 1H), 7.00-7.71 (m, 10H). MS APCI, m/z=306 (M+1), LC/MS, 2.83 min. Chiral HPLC was used to determine ee % by comparing this sample to a known sample of the racemic compound N-benzyl-N-(1-phenylprop-2-en-1-yl)cyclopentanamine. 14.99 min (97.89%) and 17.52 min (2.11%) or 96% ee. Chiral HPLC method: Chiral Technologies 10 μm Chiralpak AD column 4.6 mm×250 mm. Solvents: A=IPA, B=Hexane. Isocratic Method 7% A/B over 30 minutes at 0.6 ml/mn.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]([NH2:11])([CH3:10])[CH3:9].C([O-])(=O)C.[Na+]>CCOCC.C(OC(=O)C)(=O)C>[CH:8]([N:11]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7])([CH3:10])[CH3:9]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(C)N1C(=O)C=CC1=O
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 8.4 %

Procedure:
A cooled (5° C.) stirred solution of maleic anhydride (29.4 g, 0.30 mole) in anhydrous ether (150 mL) under nitrogen was treated dropwise over 45 min with a solution of isopropylamine (35.5 g, 0.60 mole) in anhydrous ether (100 mL) at a rate to keep the pot temp <20° C. The mixture was then stirred at 10° C. for 15 min, filtered, and the filter cake rinsed with anhydrous ether and dried in vacuo to afford a white solid. This was taken up in acetic anhydride (250 mL), treated with anhydrous sodium acetate (12.3 g, 0.15 mole), and heated to 75° C. with stirring for 4.5 h, then at 100° C. for 1.5 h. The mixture was concentrated in vacuo and the residue taken up in methylene chloride (300 mL), washed with saturated aqueous sodium bicarbonate (200 mL), water (200 mL), dried (MgSO4), and concentrated in vacuo. The residue was distilled (approx. 5 mm pressure) to afford two products; one an N-isopropylmaleimide that distilled at 82° C. (13.0 g), the other an acetate adduct of N-isopropylmaleimide that distilled at 154° C. (12.9 g). The acetate adduct was dissolved in 4:1 acetonitrile/triethylamine (100 mL), heated to 65° C. for 4 h, then concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a pad of silica gel (eluted with methylene chloride) to afford an additional 3.5 g of N-isopropylmaleimide. Total yield was 16.5 g of N-isopropylmaleimide (40%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1)N(C)C
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(C(C)N(C)C)CC4)c3c2)cc(Cl)c1O
Yield: 56 %

Procedure:
Following general procedure F, (6-bromo-4-{4-[1-(dimethylamino)ethyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (50 mg, 0.116 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.173 mmol) to afford the desired product (33 mg, 56%) as a yellow-green solid: 1H NMR (500 MHz, CD3OD) δ 8.74 (s, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.07-7.97 (m, 2H), 7.32 (d, J=2.1 Hz, 1H), 7.25 (d, J=2.1 Hz, 1H), 4.00 (s, 3H), 3.55 (d, J=12.2 Hz, 2H), 3.19 (dd, J=19.9, 7.2 Hz, 2H), 2.64-2.58 (m, 1H), 2.58-2.50 (m, 1H), 2.40 (s, 6H), 2.03 (d, J=12.7 Hz, 1H), 1.95-1.78 (m, 3H), 1.73-1.61 (m, 2H), 1.33-1.28 (m, 2H), 1.26-1.20 (m, 2H), 1.11 (d, J=6.6 Hz, 3H); ESI MS m/z 508 [C29H34ClN3O3+H]+; HPLC 97.0% (AUC), tR=10.04 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]=[CH:11][CH3:12])=[C:4](I)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])=O.[Na+].[Cl-].C([NH3+])CCC>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:9]=[C:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1
Reactant: CC=CCOc1ccc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[NH3+]
Solvent: CN(C)C=O
Product: CCc1coc2ccc(Cl)cc12
Temperature: 80 °C
Yield: 60.4 %

Procedure:
To a mixture of 4-chloro-2-iodo O-crotyl phenol (1.5 g, 4.86 mmol), sodium carbonate (12.2 mmol, 1.3 g), sodium formate (4.86 mmol, 330 mg), n-butyl ammonium chloride (5.34 mmol, 1.5 g) and DMF (10 mL) was added palladium di-acetate (0.24 mmol, 55 mg). The reaction was heated at 80° C. and maintained at that temperature overnight. After bringing the reaction to room temperature, the mixture was filtered. The filtrate was dried and evaporated to give a crude product, which was purified by silica gel chromatography (eluent:hexanes) to obtain 5-chloro-3-ethyl-benzofuran as a clear oil (60%, 530 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.O1CCCC1.[Pd]>[C:1]([NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1nccc(C=Cc2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1nccc(CCc2ccc(N)cc2)n1
Yield: 91.1 %

Procedure:
A mixture of 2-acetamido-4-[2-(4-nitrophenyl)vinyl]pyrimidine (8.52 g) in ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium on carbon (2 g) under atmospheric pressure of hydrogen gas for 6 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 2-acetamido-4-[2-(4-aminophenyl)ethyl]pyrimidine (7.0 g).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][C:12]=1[F:20].[NH2:21][C:22]1[C:23]([N:31]2[CH2:36][C@H:35]([CH3:37])[C@@H:34]([O:38][Si](C(C)(C)C)(C)C)[C@H:33]([NH:46]C(=O)OC(C)(C)C)[CH2:32]2)=[C:24]2[CH2:30][CH2:29][O:28][C:25]2=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>>[NH2:46][C@H:33]1[C@H:34]([OH:38])[C@@H:35]([CH3:37])[CH2:36][N:31]([C:23]2[C:22]([NH:21][C:17]([C:15]3[CH:14]=[CH:13][C:12]([F:20])=[C:11]([C:3]4[C:4]([F:10])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])[N:16]=3)=[O:19])=[CH:27][N:26]=[C:25]3[O:28][CH2:29][CH2:30][C:24]=23)[CH2:32]1
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@@H](N)[C@H](O)[C@@H](C)C3)CCO4)ccc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
To a mixture of 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (176 mg, 0.372 mmol), tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (152 mg, 0.317 mmol), and HATU (374 mg, 0.983 mmol) in DMF (3.0 mL) DIPEA (238 mg, 1.84 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the resulting residue, DCM (2.0 mL) was added followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (54 mg, 32%). LCMS calc. for C26H27F3N5O4 (M+H)+: m/z=530.2. found 530.0. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.70 (s, 1H), 8.34 (dd, J=8.7, 4.0 Hz, 1H), 8.18 (t, J=8.8 Hz, 1H), 7.39-7.32 (m, 1H), 7.24-7.17 (m, 1H), 4.53-4.44 (m, 2H), 4.41 (d, J=3.8 Hz, 1H), 3.89 (s, 3H), 3.36 (t, J=8.5 Hz, 2H), 3.10-3.04 (m, 1H), 3.00-2.93 (m, 1H), 2.63 (t, J=10.8 Hz, 1H), 2.58-2.51 (m, 2H), 2.46-2.38 (m, 1H), 1.66 (br, 2H), 1.48-1.36 (m, 1H), 0.69 (d, J=6.5 Hz, 3H) ppm.