Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[N:5]=[CH:4][N:3]=1.[S:10](Cl)(Cl)=O>C(Cl)(Cl)Cl.CO>[NH2:9][C:6]1[C:7]2[C:2](=[N:1][S:10][N:8]=2)[N:3]=[CH:4][N:5]=1
Reactant: Nc1ncnc(N)c1N
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1ncnc2nsnc12

Procedure:
A flask was charged with 19.78 g. (0.15 mole) of 4,5,6-triaminopyrimidine and 163.0 g. (137 mole) of thionyl chloride and the mixture stirred at reflux for 18 hours. The dark orange reaction mixture was evaporated to dryness on the rotary evaporator and to the residue was added 500 ml. water and 40 ml. methanol. The resulting solution was adjusted to a pH of 7.5-8.0 with saturated sodium bicarbonate solution and heated to reflux. The hot mixture was filtered and the filtrate cooled to 0°-5° C. in an ice-bath. The solid was collected by filtration, washed twice with 50 ml. ice water and twice with 50 ml. ether. The resulting tan product was dried in vacuo at 70° C. overnight to afford 18.2 g. (79%) of product. M.p. 247°-249° C.; tlc on silica gel in chloroform-methanol (8:1) showed one spot at Rf =0.4.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][CH2:14][CH2:15][NH2:16].[CH2:17]=O>ClCCCl>[CH3:12][O:13][CH2:14][CH2:15][N:16]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:17]
Reactant: C=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COCCN
Solvent: ClCCCl
Product: COCCN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 1,2-dichloroethane (50 ml) were dissolved p-nitro-benzaldehyde (5 g) and 2-methoxyethylamine (2.7 g), and to the mixture was added, under ice-cooling, triacetoxy sodium boro hydride (9.8 g). Under nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours, and to the mixture were added, under ice-cooling, 37% formalin (3.8 ml) and triacetoxy sodium boro hydride (10 g). Under nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. The residue was neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give N-(2-methoxyethyl)-N-methyl-4-nitrobenzylamine (5.9 g) as yellow oil.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:15]([C:17]1[O:18][C:19]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)=[O:16])=[O:8])C>O.O1CCCC1.CO>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:19]2[O:18][C:17]([C:15]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]3[C:7]([OH:8])=[O:6])=[O:16])=[CH:21][CH:20]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CCCCN1C(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1CCCCN1C(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of lithium hydroxide monohydrate (0.027 g 0.64 mmol) in water (1 mL) was added to a solution of (rac)-1-[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-piperidine-2-carboxylic acid ethyl ester (0.085 g, 0.2 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL). The mixture was stirred overnight at room temperature and then the solvents were evaporated under reduced pressure. Water and ethyl acetate were added, and the mixture was acidified to pH 2 with 1 M HCl and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered and evaporated. The residue was triturated with ether. The ether and dissolved impurities were removed by Pasteur pipette to give (rac)-1-[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-piperidine-2-carboxylic acid (66 mg, 83%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[C:19]3[C:18]([C:20]([O:22]C)=O)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:25][NH2:26]>CO.Cl>[CH2:8]([C:9]1[C:11]2=[CH:12][NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]=32)[C:20](=[O:22])[NH:26][N:25]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]cc(C(=O)CCc3ccccc3)c12
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1NN=C(CCc2ccccc2)c2c[nH]c3cccc1c23

Procedure:
A solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in dichloroethane (3 mL) was treated with 3-phenylpropionyl chloride (361 mg, 2.14 mmol) at room temperature. The orange solution was cooled to 0° C. and treated with aluminum chloride (572 mg, 4.29 mmol). The reaction mixture was stirred at room temperature for 2 h, then poured into ice-cold 1M aqueous HCl. The aqueous solution was adjusted to pH=8 with 1M NaOH, and extracted with CH2Cl2 (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl 3-(3-phenylpropionyl)-indole-4-carboxylate as a pale-yellow solid, 395 mg (90%). A solution of the 3-(3-phenylpropionyl)-4-carboxy indole (95.5 mg, 0.31 mmol) in MeOH (3 mL) and HCl (0.1 mL) was treated with hydrazine hydrate (47 mg, 0.93 mmol) and the solution was heated at reflux for 8 h. The solution was cooled in an ice/water bath and the precipitated solid was collected by filtration to give 1,5-dihydro-3-phenethyl-[1,2]diazepino[4,5,6-cd]-indol-6-one, 60.2 mg (71%). The crude product was purified by radial chromatography (2 mm SiO2, 5:1 hexanes:EtOAc) to give a yellow solid. mp 182-183.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.80 (m, 2H), 2.84 (m, 2H), 7.22 (m, 2H), 7.31 (m, 4H), 7.54 (m, 2H), 7.81 (s, 1H), 10.19 (s, 1H), 11.92 (br s, 1H); Anal. (C10H7N3O.0.1 H2O) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH:11]([Mg]Cl)([CH3:13])[CH3:12].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(C)C)cc1
Reaction time: 1 h

Procedure:
A solution of 1.5 ml 4-methoxy-benzaldehyde in 10 ml of toluene is added dropwise at 8° C. to 7.4 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran. Then the mixture is allowed to come up to ambient temperature and stirred for 1 hour. Then the reaction is stopped by the addition of semisaturated aqueous ammonium chloride solution. The phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with semisaturated aqueous ammonium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo and the product thus obtained is further reacted directly.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:5].S(Cl)([Cl:22])=O>>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:22])=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 10.3 g of 4-[(2-methylbenzoyl)amino]benzoic acid and 32 ml of thionyl chloride is refluxed for 1.5 hours. The solution is concentrated under vacuum. Toluene is added and the solvent removed under vacuum. Toluene is added and the mixture chilled and filtered to give a yellow solid, m.p. 135°-141° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])=[CH:12][CH:11]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(NC(=O)CC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1cccc2ccc(NC(=O)CC3CCCC3)cc12
Reaction time: 72 h
Yield: 81 %

Procedure:
To a mixture of methyl 4-[7-(cyclopentyl acetamido)naphth-1-ylmethyl]-3-methoxybenzoate (660 mg), methanol (23 ml) and tetrahydrofuran (23 ml) was added a solution of lithium hydroxide monohydrate (321 mg) in water (7.7 ml). Nitrogen was bubbled through the mixture for 30 seconds before it was stoppered and stirred for 72 h. The reaction mixture was evaporated and the residue taken up in 75 ml of 1:9 tetrahydrofuran:ethyl acetate and acidified with 3 ml of 6N HCl. The organic layer was washed (water, brine), dried (MgSO4) and evaporated. Recrystallization of the resulting solid from 1:9 methanol:methylene chloride and petroleum ether gave the title compound as a colorless solid (517 mg, 81%); mp 248.0°-250.0° C.
Reaction SMILES: FC(F)(F)C#[N:4].[Cl:7][C:8]1[CH:33]=CC2O[C:13]3[CH:31]=[CH:30]C=C[C:14]=3[C@@H:15]3[C@H:20]([NH:21][C:22](=O)[C:23]([F:26])([F:25])[F:24])[CH2:19][CH2:18][CH2:17][N:16]3[C:10]=2[CH:9]=1.[CH2:34]1[CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:7][C:8]1[CH:33]=[CH:35][C:36]2[O:37][C:38]3[CH:34]=[CH:30][CH:31]=[CH:13][C:14]=3[C@@H:15]3[C@H:20]([NH:21][C:22](=[NH:4])[C:23]([F:26])([F:25])[F:24])[CH2:19][CH2:18][CH2:17][N:16]3[C:10]=2[CH:9]=1
Reactant: C1CCOC1
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Reactant: N#CC(F)(F)F
Product: N=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
Trifluoroacetonitrile was added to a solution of trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (10 mg, 0.03 mmol) in 2 mL of THF for 2 h. The mixture was stirred at room temperature for 16 hr. After evaporation the crude compound was chromatographed on silica. Elution with toluene gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetimidamide (7.14 mg, 55%). Data: (m/z)=396 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:35])([F:34])[C:26]=3[C:25]([CH:36]([F:38])[F:37])=[N:24]2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.BrC1C([C@@H](NC(=O)CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1.[CH3:81][N:82]([CH3:86])[CH2:83]CN>>[Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:34])([F:35])[C:26]=3[C:25]([CH:36]([F:37])[F:38])=[N:24]2)[CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:81][N:82]([CH3:86])[CH3:83])=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: CN(C)CCN
Agent: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: CN(C)CCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (16A) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 12C and N,N-dimethylethane-1,2-diamine. MS (m/z) 686.00 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:17]=[N:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:14]2[O:22][C:23]([CH3:27])([CH3:26])[O:24][CH2:25][C:13]=12)=[O:11].C(=O)(O)[O-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]([OH:11])[C:12]2[CH:17]=[N:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:14]3[O:22][C:23]([CH3:26])([CH3:27])[O:24][CH2:25][C:13]=23)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COC(=O)c1ncc(C=O)c2c1OC(C)(C)OC2
Agent: O=C([O-])O
Product: COC(=O)c1ncc(C(O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
A 4-fluorophenyl magnesium bromide solution (0.438 mL of 1M in tetrahydrofuran, 30.0 mmol, 1.1 eq) at −78° C. was added to a methyl 5-formyl-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate solution (0.100 g, 0.398 mmol, 1 eq. in 5.0 mL of tetrahydrofurane). The reaction mixture was stirred for 20 min. at −78° C. A saturated bicarbonate solution was added and reaction mixture was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure yielding 0.065 g of crude product methyl 5-((4-fluorophenyl) (hydroxy)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate 2a (47% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH3:24]>CN(C)C=O>[ClH:1].[CH2:21]([N:10]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:9]1[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=2[S:7][CH:8]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: Clc1ccc2c(Nc3ccncc3)csc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(c1ccncc1)c1csc2cc(Cl)ccc12
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 110.2 %

Procedure:
6-Chloro-3-(4-pyridinylamino)benzo[b]thiophene (5 g, 19 mmol) was added portionwise as a powder to a suspension of sodium hydride (60% oil dispersion, 0.8 g, 20 mmol, washed with heptane) in 50 mL of dimethylformamide. After the anion formation was completed, 1-bromobutane (2.8 g, 20 mmol) was added. After stirring one hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, and dried (anhydrous magnesium sulfate), filtered and concentrated. Elution of the residue through silica with 5% methanol in ethyl acetate via flash column chromatography afforded 3.7 g of an oil. Elution through alumina with ether via column chromatography afforded 3.3 g of an oil. Conversion to the hydrochloride salt in 10% methanol in ether afforded 3.2 g of white crystals, mp 259°-260° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH2:12][Br:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Br)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(Br)c1CBr
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.6 %

Procedure:
Methyl 3-bromo-2-methylbenzoate (7.45 g, 32.5 mmol) was dissolved in CCl4 (94 ml) and N-bromosuccinimide (6.67 g, 37.5 mmol) and benzoyl peroxide (0.38 g, 1.6 mmol) were added. The reaction was heated to 75 C-85 C, stirred for 3 hours and 45 minutes, cooled to room temperature, and filtered. The filtrate was concentrated and purified on SiO2 (Biotage instrument; 0%->20% EtOAc/hexanes) to give methyl 3-bromo-2-(bromomethyl)benzoate (10.07 g, 100%).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.[Br-].[K+]>CN1CCCC1=O>[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:3][CH:2]([F:5])[F:1])=[CH:9][CH:8]=1
Reactant: FC(F)CCl
Reactant: NCc1ccc(Cl)nc1
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: FC(F)CNCc1ccc(Cl)nc1
Temperature: 120 °C
Yield: 70.8 %

Procedure:
13.7 g (0.135 mol) of 2,2-difluoro-1-chloroethane, 10 g (0.067 mol) of 1-(6-chloropyridin-3-yl)methanamine and 8.2 g of triethylamine are initially charged with 31 g of N-methylpyrrolidone. In addition, 4 g (0.033 mol) of potassium bromide are added. The mixture is heated to 120° C. under autogenous pressure in an autoclave for 16 hours and then cooled again to 80° C. The N-methylpyrrolidone is distilled off at 80° C. under reduced pressure and the reaction mixture is poured onto 20 ml of 32% hydrochloric acid. The mixture is concentrated to dryness under reduced pressure and then adjusted to pH 12 with 10 ml of 45% NaOH. The mixture is extracted three times with 30 ml of toluene and the organic phases are distilled under reduced pressure. This gives 9.8 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (corresponds to 71% yield).
Reaction SMILES: [Mg].II.Br[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([Cl:13])[CH:7]=1.[F:14][C:15]([F:32])([F:31])[C:16](=[O:30])[CH2:17][C:18]([C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[O:28][CH3:29])([CH3:20])[CH3:19]>C(OCC)C>[Cl:12][C:10]1[CH:11]=[C:6]([CH2:5][C:16]([OH:30])([CH2:17][C:18]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])([CH3:20])[CH3:19])[C:15]([F:14])([F:32])[F:31])[CH:7]=[C:8]([Cl:13])[N:9]=1
Reactant: Clc1cc(CBr)cc(Cl)n1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(Cl)nc(Cl)c1)C(F)(F)F

Procedure:
To a 100 mL dry round bottom flask was added 73 mg (3.0 mmol) of magnesium powder, a couple of I2 crystals, and 5 mL of dry diethyl ether, and the mixture was allowed to stir under argon. 4-Bromomethyl-2,6-dichloropyridine (723 mg, 3.0 mmol) in 10 mL of diethyl ether was added dropwise through a dropping funnel and the resulting mixture was heated to reflux for 1 hour. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (278 mg, 1.0 mmol) (Example 1) in diethyl ether (5 mL) was carefully added dropwise through a dropping funnel and the mixture was allowed to stir to reflux temperature for 4 hours and then overnight (16 hours) at room temperature. The reaction was quenched with the addition of 3 mL of aqueous NH4Cl solution, and the resulting mixture was extracted with three 30 mL portions of EtOAc, washed with H2O (10 mL) and brine (10 mL), and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using an EtOAc-hexanes gradient. Combined product fractions were concentrated in vacuo to afford the desired product which was further purified by preparative-HPLC using a gradient of 80%-100% (CH3CN-water) in 15 minutes and a flow rate of 20 mL/min to afford 76 mg of the title compound (17.2% yield) as a yellowish liquid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:22]([NH:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:58][C@H:56]([OH:57])[CH2:55][O:54][C:51]3[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=3)=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 17.6 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfonyl}-N-octyl-1-piperidinecarboxamide (1.53 g, 3.612 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (1.39 g, 3.431 mmol) according to Procedure G to give the title compound (eluant: 20: chloroform-ethanol) (0.500 g, 0.604 mmol).
Reaction SMILES: O[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)c1ccccc1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Br)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a cooled (0° C.) solution of 0.425 g (2.19 mmol) of the product of Step B dissolved in 10 mL of dichloromethane was added 0.717 g (2.74 mmol) of triphenylphosphine followed by 0.908 g (2.74 mmol) of carbon tetrabromide. After 30 minutes the reaction was allowed to warm to room temperature and stirring was continued for 2 hours. The raction mixture was evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.373 g (66%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH3:30]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: CCOc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOc1ccccc1O[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-ethoxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.16 mg, 15.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.52 (s, 1H), 7.40-7.33 (m, 4H), 7.30-7.20 (m, 3H), 6.97 (apparent d, 1H, J=7.7 Hz), 6.88 (m, 2H), 6.68 (m, 2H), 5.21 (m, 1H), 4.11 (q, 2H, J=7.3 Hz), 3.37 (m, 2H), 2.71 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.49 (t, 3H, J=7.3 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 501.4 (M+H)+.
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=O)[CH2:7][C:8]([O:10]C)=O.[C:13]([O:18][CH2:19]C)(=[O:17])/[CH:14]=[CH:15]/[CH3:16].C(O)(=O)C.[CH:25]([NH2:27])=[NH:26].Cl>CO.O>[OH:5][C:6]1[C:7]([CH:15]([CH3:16])[CH2:14][C:13]([O:18][CH3:19])=[O:17])=[C:8]([OH:10])[N:27]=[CH:25][N:26]=1
Reactant: C/C=C/C(=O)OCC
Reactant: N=CN
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)CC(C)c1c(O)ncnc1O
Temperature: 67.5 °C
Reaction time: 1.25 h

Procedure:
Charge anhydrous methanol (50 mL) to a flask followed by sodium methoxide (5.4 g, 0.1 mol, 0.3 equiv) and heat the mixture to 65-70° C. Add propanedioic acid dimethyl ester (44 g, 0.33 mol, 1.0 equiv) drop wise and the stir mixture at 65-70° C. for 10-30 min. Add ethyl crotonate (33.4 g, 0.33 mol, 1.0 equiv) drop wise over 1-2 h, and stir the mixture at 65-70° C. for 1-1.5 h. Cool the reaction mixture to −20° C. to −10° C. In a separate flask, dissolve sodium methoxide (54 g, 1.0 mol, 3.0 equiv) in anhydrous methanol (180 mL) and stir the mixture for 20-30 min. Cool the mixture to −20° C. to −10° C., and add formamidine acetate (40 g, 0.4 mol, 1.2 equiv). Add this solution drop wise to the first solution over a period of 1 h while maintaining the temperature from −20° C. to −10° C. Stir for 1-2 h and then warm the mixture to 20-25° C. over 3-4 h. Stir the mixture for 2-8 h, and then charge a solution of concentrated HCl (110-130 g) in water (330 g-390 g) while keeping the reaction temperature <10° C. Stir the suspension for 30-60 min at <10° C. and filter. Wash the filter cake with water (70 mL) and slurry the filter cake with methanol (56 g). Filter to collect methyl 3-(4,6-dihydroxypyrimidin-5-yl)butanoate (55.6 g, 72%). MS (ES) m/z=213 [M]+.