Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc(Cl)cc2)cnc1N
Yield: 100.3 %

Procedure:
A solution of 1.19 g of 2-amino-5-(4-chlorophenyl)-3-nitro-pyridine in 17 ml of ethanol is treated with 5.5 g of SnCl2.2H2O at 90° C. for 17 h under a nitrogen atmosphere. Thereafter, the solution is concentrated in vacuo to dryness. The residue is dissolved in 300 ml of water and adjusted to pH 8 using a 1.0 M solution of aqueous sodium hydroxide. Subsequently, the aqueous layer is extracted four times each with 50 ml of ethyl acetate. The combined organic phases are extracted once with 50 ml of brine, dried using MgSO4, filtered with suction, and evaporated to dryness to yield 1.05 g of the pure title compound of m.p. 178° C. MS: 220.3 (MH+). MS: 220.3/222.3 (MH+, 100%/20%). TLC: Rf=0.30 (dichloromethane/methanol 5:1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].[Br:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH2:33]Br)[CH:24]=1>CS(C)=O>[Br:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH2:33][N:8]2[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]3[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]2=3)[CH:24]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Br)cc1CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
(R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (200 mg, 0.882 mmol) (PREPARATION x2, 200 mg, 0.882 mmol) was dissolved in DMSO (5 mL). Sodium tert-butoxide (102 mg, 1.059 mmol) was then added to give a brown solution. After 5 minutes, methyl 4-bromo-2-(bromomethyl)benzoate (299 mg, 0.971 mmol) was added dropwise. The reaction was stirred overnight at room temperature, then quenched with aqueous saturated NH4Cl. The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a white foam (164 mg, 41%). ESI-MS m/z [M+H]+ calc'd for C18H18BrClN4O3, 453.04. found 453.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][N:6]=[CH:5]2.C[Si](C)(C)N[Si](C)(C)C.[Li].Br[CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN(C=O)C>[C:31]([Si:28]([CH3:30])([CH3:29])[O:27][CH2:26][CH2:25][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH:5]=[N:6]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1cc2cn[nH]c2cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CN(C)C=O
Product: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 50.7 %

Procedure:
5-Methyl-6-nitro-1H-indazole (354 mg, 2.0 mmol) was dissolved in DMF (10 ml) and the mixture was cooled to 0° C. with stirring. Lithium hexamethyldisilazane (2.2 ml of 1.0 M toluene solution) was added dropwise. The mixture was allowed to stir for five minutes, and then (2-bromoethoxy)-tert-butyldimethylsilane (0.52 ml, 2.4 mmol) was added. The mixture was stirred for 30 minutes at 0° C., then allowed to warm to room temperature with stirring for four hours. The reaction was quenched with pH2 buffer solution, and the mixture was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 hexanes/ethyl acetate) to give 340 mg (50.7%) of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indazole as a white powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].Cl[CH2:15][CH2:16][OH:17].C1(C)C=CC=CC=1>CS(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:15][CH2:16][OH:17]
Reactant: Oc1ccc2ccccc2c1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: OCCOc1ccc2ccccc2c1
Yield: 70 %

Procedure:
The reaction set-up consisted of a three necked round bottom flask, equipped with a thermometer, condenser and a mechanical stirrer, and a dropping funnel. 2-Naphthol, 100 g (0.6936 moles), was dissolved in 60 mL of dimethyl sulfoxide. Sodium hydroxide, 27.7 g (0.6936 moles), was carefully added to the solution. Then 2-chloroethanol, 61.4 g (0.7629 moles), was slowly added, keeping the reaction temperature at 80° C. The reaction was followed by GC. After >>80% conversion was achieved, the reaction was worked-up by adding toluene and extracting the unreacted naphthol with 5% aqueous NaOH. The product was then recrystallized in ethanol or distilled under vacuum (70-80% yield).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].N1C=CN=C1.[CH3:11][C@H:12]([CH2:28][CH3:29])[C@:13]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1.O>CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]([O:20][Si:2]([CH3:4])([CH3:3])[CH3:1])([C@H:12]([CH3:11])[CH:28]=[CH2:29])[CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:22][CH:23]=1
Reactant: CC[C@@H](C)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=C[C@@H](C)[C@@](Cn1cncn1)(O[Si](C)(C)C)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 114.7 %

Procedure:
2.47 ml (19.4 mmole) of trimethylsilyl chloride and 1.7 g (24.3 mmole) of imidazole were added to a solution of 900 mg (3.24 mmole) of (2R*,3R*)-3-methyl-2-(4-chlorophenyl) -(1H-1,2,4-triazol-1-yl)-2-pentanol in 20 ml of N,N-dimethylformamide, and then the mixture was stirred at 50° C. for 4 hours. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure to give 1.3 g of the title compound in the form of a crude oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[O:50])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([O:57][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][C:4]1=[O:68])[CH3:2].F>C(#N)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[O:50])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:68])[CH3:2]
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C(C)C)(C(C)C)C(C)C)C2C)C(OC)CC3C)CCC1=O
Agent: F
Solvent: CC#N
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1=O

Procedure:
To a stirred solution of 17-ethyl-1-hydroxy-12-[2'-(3"-propyloxy-4"-oxocyclohexyl)-1'-methylvinyl]14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone from Example 96 in acetonitrile was added hydrofluoric acid at room temperature. The reaction progress is monitored by tlc analysis and then the reaction mixture is quenched with sat'd aqueous sodium bicarbonate. The organic layer is separated and the aqueous layer is extracted with ethyl acetate three times. Combined organic layers are washed (sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel column chromatography) gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:17][CH2:16][N+:11]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:18][C:19]1[N:20]=[C:21]([CH3:25])[NH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][C:19]1[N:20]=[C:21]([CH3:25])[N:22]([CH2:12][CH2:13][CH2:14][CH2:15][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=3)[CH2:17][CH2:16]2)[C:23]=1[Cl:24]
Reactant: Cc1nc(Cl)c(Cl)[nH]1
Reactant: Fc1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncc(F)cn2)CC1
Yield: 85.2 %

Procedure:
A mixture of 3.17 g (0.01 mol) of 8-(5-fluoro-2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane, 2.26 g (0.015 mol) of 4,5-dichloro-2-methyl-1H-imidazole and 76 g (0.02 mol) of potassium carbonate in 80 ml of dimethylformamide is maintained at reflux for 12 hours. The mixture is subsequently evaporated to dryness and the resulting crude product is redissolved in chloroform and washed repeatedly with water. The organic phase is dried and evaporated, and then the resulting crude product is purified by chromatography on a column of silica gel. 3.3 g (85% yield) of 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]piperazin-1-yl}-5-fluoropyrimidine are obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(=O)([O-])[O-:30].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:30])=[CH:15][C:14]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COc1ncccc1-c1cc(C#N)ccc1Oc1cnc(OC(C)C)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1cnc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 4-[(5-chloro-6-isopropoxypyridin-3-yl)oxy]-3-(2-methoxypyridin-3-yl)benzonitrile (Preparation 26, 534 mg, 1.35 mmol) in DMSO (10.0 mL) was added potassium carbonate (560 mg, 4.05 mmol) and a 30% aqueous solution of hydrogen peroxide (690 μL, 6.74 mmol). The reaction was stirred at room temperature for 1 hour. Water (50 mL) was added to the reaction mixture resulting in the formation of a white precipitate. The precipitate was filtered, washed with water (50 mL) and dried in vacuo to obtain the title compound as a colourless solid (436 mg, 85%), which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:19][CH:18]=1)[C:6](=[O:15])[CH2:7][C:8]([C:11]([O:13]C)=[O:12])([CH3:10])[CH3:9])[CH2:2][CH2:3][CH3:4].C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC.[OH-].[K+]>CC1C=CC=CC=1C>[CH2:1]([N:5]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[NH:46][N:45]=[N:44][N:30]=2)=[CH:21][CH:22]=1)[C:6](=[O:15])[CH2:7][C:8]([C:11]([OH:13])=[O:12])([CH3:9])[CH3:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CC(C)(C)C(=O)OC
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)CC(C)(C)C(=O)O

Procedure:
A solution of 4.0 g (9.8 mmol) of 3-methoxycarbonyl-3-methyl-butanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide and 4.3 g (13 mmol) of tributyltin azide in 80 ml of o-xylene is reacted analogously to Example 1 for 24 hours. For hydrolysis, the reaction mixture is stirred with 50 ml of 2N potassium hydroxide solution at from 40 bis 50° for 4 hours. The aqueous phase is separated and acidified with 2N hydrochloric acid, and the oil which separates is extracted with ethyl acetate. Washing of the ethyl acetate solution with water, drying over MgSO4 and concentration by evaporation yield 3-carboxy-3-methyl-butanoic acid N-butyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amide in the form of a colourless foam that has an Rf value of 0.25 [toluene/isopropanol/glacial acetic acid (170:30:2)].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:30][C:29]5[CH:32]=[CH:33][C:34]([N+:35]([O-:37])=[O:36])=[C:27]([F:26])[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)cccc3[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(F)c5)CC4)cccc3[nH]2)cc1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a stirring solution of 2-(4-tert-Butyl-phenyl)-4-piperazin-1-yl-1H-benzoimidazole (0.857 g, 2.56 mMol) and 3-Fluoro-4-nitro-benzaldehyde (0.52 g, 3.07 mMol) in N-methylpyrrolidinone (20 mL) was added sodium triacetoxyborohydride (1.36 g, 6.40 mMol) and the solution stirred overnight. Upon arrival the solution was diluted with ethyl acetate (200 mL). The mixture was washed with saturated sodium bicarbonate solution (75 mL), water (75 mL), and brine (75 mL). The organic layer was then dried with magnesium sulfate, filtered, concentrated, and purified by flash column chromatography on silica gel using 40% ethyl acetate in hexane as the eluant to yield 850 mg (68% yield) of 2-(4-tert-Butyl-phenyl)-4-[4-(3-fluoro-4-nitro-benzyl)-piperazin-1-yl]-1H-benzoimidazole as a light yellow solid. 1H NMR (DMSO-d6): δ=12.69 (s, 1H), 8.16 (t, 1H, J=8.2 Hz), 8.04 (d, 2H, J=8.5 Hz), 7.59 (m, 1H), 7.55 (d, 2H, J=8.5 Hz), 7.47 (d, 1H, J=8.6 Hz), 7.03 (m, 2H), 6.50 (dd, 1H, J=7.0, 1.8 Hz), 3.71 (s, 2H), 3.60 (br s, 4H), 2.66 (br s, 4H), 1.33 (s, 9H). LC/MS (Method A), rt=1.24 mins., purity=100%, calculated mass=487, [M+H]+=488, [M−H]−=486.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8]([N:14]([CH3:24])[CH2:15][CH:16]2[CH2:23][CH2:22][C:19]3([CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:9][C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].[C-]#N.[K+].C1N2CC[N:30](CC2)[CH2:29]1.O>CS(C)=O>[CH2:1]([O:4][C:5]([C:7]1[C:8]([N:14]([CH3:24])[CH2:15][CH:16]2[CH2:23][CH2:22][C:19]3([CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:9][C:10]([C:29]#[N:30])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C1CN2CCN1CC2
Reactant: C=CCOC(=O)c1cnc(Cl)nc1N(C)CC1CCC2(CC1)CC2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOC(=O)c1cnc(C#N)nc1N(C)CC1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the 2-chloro-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxylic acid allyl ester (1.1 mmol) in DMSO (2.0 mL) are added KCN (1.6 mmol), DABCO (0.3 mmol), and H2O (0.2 mL) at room temperature. The reaction mixture is stirred at room temperature for 3 h and the reaction is quenched by the addition of water. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the title compound.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([Cl:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[Cl:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(Cl)Br
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: ClCCCCCCCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of lithium tetrachlorocuprate [THF 33 L, lithium chloride (0.87 kg, 19.3 mol), cupric chloride (1.4 kg, 10.4 mol)] was added to a solution of benzylmagnesium chloride (160 L of 1.86M, 298 mol) in tetrahydrofuran at 15° C., and the mixture stirred for 30 min. Bromochlorohexane in toluene (85.5 kg of solution, 55% w/w by assay, 47.1 kg, 236 mol) was added over 3 h while maintaining the temperature between 15°-20° C. Stirring was continued for a further 1.25 h. 10% Ammonium chloride solution (263 L) was added over 1 h, maintaining the temperature below 30° C. The phases were separated and the organic phase further washed with ammonium chloride solution (170 L) and 20% sodium chloride solution (3×197 L). The organic solution was concentrated under vacuum to leave an oil (56.8 kg, 77% pure by HPLC assay, 88% corrected yield), which was distilled (b.p. 129°-132° C., 2 mbar) to yield the title compound (70%, 99% pure by GC assay).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([Cl:18])[N:10]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:28])[C:23]([O:26][CH3:27])=[N:24][CH:25]=1>C(#N)C>[Cl:18][C:11]1[N:10]=[C:9]([NH:28][C:22]2[C:23]([O:26][CH3:27])=[N:24][CH:25]=[C:20]([Cl:19])[CH:21]=2)[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1
Reactant: COc1ncc(Cl)cc1N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ncc(Cl)cc1Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
Triethylamine (2.7 mL) and a catalytic amount of 4-diaminopyrimidine were added to a solution of 2,6-dichloro-3-nitropyridine (639 mg, 3.31 mmol) and 5-chloro-2-methoxy pyridin-3-amine (Preparation 23, 501 mg, 3.16 mmol) in acetonitrile (20 mL) and the resulting mixture was stirred overnight at 90° C. Solvent was then removed under reduced pressure until a solid precipitated. The solid was filtered, washed with acetonitrile and dried. The solid was then treated with dichloromethane, filtered, washed with more dichloromethane and the combined filtrate and washings were concentrated to dryness under reduced pressure to yield the title compound (390 mg 30%) as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH:14]=[CH2:15])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH3:15])[CH3:2]
Reactant: [H][H]
Reactant: C=CCc1ccccc1OCC(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccccc1OCC(=O)OCC
Yield: 97.5 %

Procedure:
A solution of (2-allyl-phenoxy)-acetic acid ethyl ester (5.8 g, 26.3 mmol) in ethanol (200 mL) was treated with 5% Pd/C (59 mg) and hydrogen at ambient temperature for overnight. The mixture was filtered and concentrated to give the title compound (5.7 g, 98%). 1H NMR (400 MHz, CDCl3) • 7.16˜7.10 (m, 2H), 6.94˜6.89 (m, 1H), 6.71 (d, J=8.1 Hz, 1H), 4.53 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H), 1.71˜1.60 (m, 2H), 1.29 (t, J=7.0 Hz, 2H), 0.96 (t, J=7.0 Hz, 3H); MS (ES) m/e 406.18 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22]>>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH:8][C:21](=[O:22])[C:20]1[C:19]([F:18])=[CH:27][CH:26]=[CH:25][C:24]=1[F:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1c(F)cccc1F

Procedure:
L-tyrosine tert-butyl ester (10.0 g) was acylated with 2,6-difluorobenzoyl chloride in a similar manner as described Example 1-(5) to give N-(2,6-difluorobenzoyl)-L-tyrosine tert-butyl ester (15.9 g). mp. 145-148° C.; IR (Nujol) 1728, 1638 cm1; MS (APCI) m/z 395 (M+NH4), 378 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[CH:23][C:22]=2[CH2:26][CH2:27][C:28](O)=[O:29])=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:13][C:9]1[N:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:22]3[CH:23]=[N:24][O:25][C:21]=3[C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Reactant: Cc1nccn1-c1ccc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 5-amino-2-(2-methyl-1-imidazolyl)pyridine (0.40 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.58 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.45 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.54 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[6-(2-methyl-1-imidazolyl)-3-pyridyl]-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.59 g, yield 63%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 193–194° C.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH:25]=[CH:24]1>C1C=CC=CC=1>[CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:23](=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N)c1
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(NC(=O)/C=C\C(=O)O)c1
Yield: 92 %

Procedure:
A stirred mixture of 0.907 g. of N-decyl-3-(3-aminophenyl)propenamide and 25 ml. of benzene was heated on a steam bath until a solution was obtained. To this solution was then added 0.358 g. of maleic anhydride in one portion. In about 30 seconds a solid precipitated. The mixture was allowed to cool and then the solid was recovered by filtration. The solid was recrystallized from acetic acid, to give 1.1 g. (92% yield) of the title compound, melting point 187°-188° C. The IR spectrum (KBr disc) showed absorptions at 3279, 2899, 1724, 1653, 1626, 1587 and 1563 cm-1. The NMR spectrum (in DMSO-d6) showed absorptions at 0.91 (m, 3H), 1.24 (s, 16H), 3.18 (m, 2H), 6.50 (m, 4H), 7.42 (m, 4H), 8.11 (m, 2H) and 10.50 (s, 1H) ppm.