Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:16](OCC)=[O:17])=[N:12][C:13]=1[O:14][CH3:15].O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:16]=[O:17])=[N:12][C:13]=1[O:14][CH3:15]
Reactant: CCOC(=O)c1ccc(Cl)c(OC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C=O)ccc1Cl
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
Lithium aluminum hydride (2.54 g) was added in small portions to a solution of ethyl 5-chloro-6-methoxypyridine-2-carboxylate (22.3 g) in tetrahydrofuran (223 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction solution under ice-cooling. After filtration through celite, the filtrate was concentrated under reduced pressure. Brine was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. Manganese dioxide (116.4 g) was added to a solution of the residue in chloroform (223 mL), and the mixture was stirred at 60° C. for one hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was suspended with hexane, stirred and then filtered. The filtrate was concentrated under reduced pressure. The same operation was further repeated three times. The resulting solids were combined and dried under reduced pressure to give the title compound as a white solid (14.7 g, 83%).
Reaction SMILES: [OH:1][C:2]1([CH2:13][N+:14]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CO.[H][H]>[Pd].C(O)(=O)C>[NH2:14][CH2:13][C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)N1CCC(O)(CN)CC1

Procedure:
A mixture of 73 parts of ethyl 4-hydroxy-4-(nitromethyl)-1-piperidinecarboxylate, 400 parts of methanol and 150 parts of acetic acid was hydrogenated in the Parr-apparatus with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. To the residue was added crushed ice and the whole was alkalized with potassium hydroxide. The aqueous phase was salted out with potassium carbonate and the product was extracted with benzene. The extract was dried, filtered and evaporated, yielding 63.5 parts of ethyl 4-(aminomethyl)-4-hydroxy-1-piperidinecarboxylate; mp. ±82° C. (intermediate 6).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[C:11]1([CH:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>C(O)CCC>[C:29]1([CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][NH:28][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[N:9][N:10]=4)[N:7]=3)[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Clc1ccc2nncn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C(OC2CCN(CCCNc3ccc4nncn4n3)CC2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 48.8 %

Procedure:
0.464 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine and 1.26 g of 4-(diphenylmethoxy)-1-piperidinepropanamine were suspended in 20 ml of 1-butanol; 0.62 ml of N-ethyldiisopropylamine was added, followed by refluxing under heating for 12 hours. After ice water and sodium hydrogen carbonate were added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated; the crystal obtained was washed with ethyl acetate and dried to yield 0.648 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=O)[NH:7][CH:8]=1)[CH3:2].[Cl:11]C1NC(=O)C(C)=C(C)N=1>>[Cl:11][C:6]1[NH:5][C:4](=[O:10])[C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: Cc1nc(Cl)[nH]c(=O)c1C
Reactant: CCc1c[nH]c(=O)[nH]c1=O
Product: CCc1cnc(Cl)[nH]c1=O
Yield: 67 %

Procedure:
The title compound was prepared in 67% yield from 5-Ethyl-1H-pyrimidine-2,4-dione utilizing a method analogous to the preparation of 2-chloro-5,6-dimethyl-3H-pyrimidin-4-one (see Lee, et al., WO 9605177). 1H NMR (400 MHz, DMSO-d6): δ13.21 (br s, 1H), 7.90 (br s, 1H), 2.39 (q, 2H, J=7.6 Hz), 1.08 (t, 3H, J=7.6 Hz). MS (ES) [m+H] calc'd for C6H7N2OCl, 159, 161; found 159, 161.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH3:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@H:18]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH3:16]
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (96 mg, 0.37 mmol), 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (125 mg, 0.40 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (225 mg, 0.48 mmol) in chloroform (4 mL). DIEA (330 μL, 1.89 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (98 mg, 0.13 mmol, 34%): LC-MS (ES) m/z=535 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[CH:4][CH:3]=1.[C:21](=O)(O)[O-].[Na+]>C(O)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[CH:21]=[N:20][C:5]2=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: Nc1ccc(Cl)nc1NCc1ccc2ncccc2c1
Agent: [Na+]
Solvent: O=CO
Product: Clc1ccc2ncn(Cc3ccc4ncccc4c3)c2n1
Temperature: 300 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Intermediate 9 (0.200 g, 0.702 mmol) was dissolved in formic acid (1.0 ml) and heated to 300° C. and stirred for 12 h. The reaction mixture was poured into ice water and pH adjusted to 7-8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as yellowish brown solid (0.200 g, 97% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ8.88 (dd, J=4.0, 1.3 Hz, 1H), 8.70 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.73 (dd, J=8.7, 1.7 Hz, 1H), 7.52 (dd, J=8.3, 2.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 5.69 (s, 2H).
Reaction SMILES: [C:1]([NH:4][CH:5]([PH:17]([OH:19])=[O:18])[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].[H-].[Na+].[CH2:22](I)[CH:23]([CH3:25])[CH3:24].C(O)(=O)C>CS(C)=O>[C:1]([NH:4][CH:5]([PH:17]([OH:19])=[O:18])[C:6]([CH2:22][CH:23]([CH3:25])[CH3:24])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(NC(C)=O)[PH](=O)O
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCOC(=O)C(CC(C)C)(C(=O)OCC)C(NC(C)=O)[PH](=O)O
Temperature: 10 °C
Yield: 44 %

Procedure:
12.0 g of diethyl 2-[(acetamido)(hydroxyphosphinyl)methyl]malonate were dissolved in 100 ml of dry dimethyl sulphoxide and the solution was cooled to 10° C. while stirring under a nitrogen atmosphere. 3.2 g of 60% sodium hydride in mineral oil were added, the mixture was stirred at room temperature for 2 hours and then 8 g of isobutyl iodide were added. The mixture was stirred at room temperature in the dark for 20 hours and 20 ml of glacial acetic acid were added. The volatiles were removed by evaporation in a high vacuum and the resulting semi-solid residue was dissolved in 100 ml of water containing 15 ml of 50% hypophosphorous acid. The solution was extracted eight times with ethyl acetate and the combined extracts were dried over sodium sulfate and evaporated. The residue was dissolved in dichloromethane and the solution was washed in sequence with water and saturated sodium chloride solution. The dichloromethane solution was dried over sodium sulfate and evaporated, and the residue was crystallized from diethyl ether/n-hexane to give 6.28 g of diethyl 2-[(acetamido)-(hydroxyphosphinyl)methyl]-2-isobutylmalonate in the form of a white solid; MS: 352 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:13]=1)[C:8](O)=O)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[Br:33]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:33][CH2:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)n1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)n1

Procedure:
Reaction Scheme 13 provides an example for the preparation of 2,6-di-tert-butylisonicotinic acid (Compound C3) which is a reagent in accordance with Formula 8 for the preparation of several preferred compounds of the present invention. Thus, 2,6-di-tert-butyl-4-methylpyridine (available commercially from Aldrich Chemical Co.) is reacted with N-bromosuccinimide and benzoyl peroxide to provide 4-bromomethyl-2,6-di-tert-butylpyridine (Compound A3). Compound A3 is reacted with base (sodium hydroxyde) to yield the coresponding hydroxymethyl compound (Compound B3), which is thereafter oxidized in a Jones oxidation reaction to give 2,6-di-tert-butylisonicotinic acid (Compound C3). ##STR11##
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 1.5 h

Procedure:
To a suspension of 2-amino-5-methoxy-benzoic acid (8.0 g, 47.8 mmol) in toluene (100 mL) was added a solution of phosgene (20%, 50.0 mL) in toluene and triethyl amine (13.40 mL). The reaction mixture was heated at 80 C. for 1.5 h. The precipitated product was filtered and washed with hexanes and toluene and dried to give 9.00 g of 6-methoxy-1H-benzo[d][1.3]oxazine-2,4-dione as a light brown solid. This was used directly for the next step.
Reaction SMILES: Br[CH2:2][C:3]1[NH:4][C:5](=[O:18])[NH:6][C:7]=1[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[ClH:19].Cl.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[ClH:19].[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:7]2[NH:6][C:5](=[O:18])[NH:4][C:3]=2[CH2:2][N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:29][CH2:30]2)=[O:17])=[CH:10][CH:11]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CN2CCN(c3ccccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 6.2 g of 4-(bromomethyl)-1,3-dihydro-5-(4-methoxybenzoyl)-2H-imidazol-2-one, 5.0 g of 1-(2-methylphenyl)piperazine dihydrochloride and 5.4 g of potassium carbonate in 100 ml of ethanol is stirred at room temperature for 24 hours. Water is added to the reaction mixture and the precipitate which forms is separated by filtration. The solid is then suspended in 2-propanol, 1 equivalent of hydrochloric acid is added, and the resulting solid is separated and recrystallized from 2-propanol/water to give 1,3-dihydro-4-(4-methoxybenzoyl)-5-[[4-(2-methylphenyl)-1-piperazinyl]methyl]-2H-imidazol-2-one hydrochloride melting at about 223°-225° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3cccc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (136) (44 mg, 0.19 mmol) was coupled with aniline (60) (40 mg, 0.21 mmol) using Method D. The residue was purified by column chromatography eluting with a stepped gradient of 10-15% EtOAc in heptane to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([NH2:30])=[N:27][C:26]=2[CH:31]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([NH:30][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=3)=[N:27][C:26]=2[CH:31]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: Nc1nc2cc(Cl)ccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2nc3cc(Cl)ccc3o2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 5-chloro-1,3-benzoxazol-2-amine as starting materials and by operations similar to those of Example 242-1 and Example 242-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=20:1). Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [N:1]1(C(N2C=CN=C2)N)C=CN=[CH:2]1.[NH2:13][C:14]1[C:23]([OH:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>C1COCC1>[NH2:1][C:2]1[O:24][C:23]2[C:14](=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:20]=[C:21]([CH3:25])[CH:22]=2)[N:13]=1
Reactant: NC(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1cc(C)cc(O)c1N
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)cc2oc(N)nc12
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of di (1H-imidazole-1-yl)methanamine (1.56 g, 9.67 mmol) in THF (30 mL) was added methyl 2-amino-3-hydroxy-5-methylbenzoate (1.40 g, 7.73 mmol) at room temperature and the resulting reaction mixture was heated at reflux for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), treated with saturated aqueous ammonium chloride (25 mL), and then extracted with CH2Cl2 (2×100 mL). The combined organic phase was washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford a yellow solid. The solid was triturated from CH3OH to afford methyl 2-amino-6-methylbenzoxazole-4-carboxylate (0.717 g, 45%). 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[CH2:17]([O:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)[CH3:18].C(O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[CH2:17]([O:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)[N:29]=1)[CH3:18]
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Yield: 59.6 %

Procedure:
3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (1.00 g, 4.54 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-benzoic acid ethyl ester (1.29 g, 4.13 mmol) were dissolved in ethanol (40.00 mL, 685 mmol) and 10-camphorsulfonic acid (1.15 g, 4.95 mmol) was added. The reaction was microwaved on 300 watts, 120° C. for 40 minutes and then concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and washed with sat. NaHCO3 (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-40% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester as a yellow solid (1.22 g, 60%). m.p.=78-80° C.; LCMS (m/e) 496 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.16 (s, 1H), 8.85 (d, 1H, J=8.5 Hz), 8.14 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 7.56-7.45 (m, 1H), 7.35 (s, 1H), 7.30-7.20 (m, 1H), 7.13-7.01 (m, 2H), 6.93 (s, 1H), 4.45 (q, 2H, J=7.1 Hz), 3.60-3.50 (m, 2H), 3.39 (s, 3H), 3.0-2.88 (m, 4H), 2.80-2.67 (m, 6H), 1.45 (t, 3H, J=7.1 Hz).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I-].[CH:12]1([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:37][O:38][C:39]1[N:44]=[C:43]([C:45]([C:47]2[CH:52]=[CH:51][C:50]([S:53][CH3:54])=[CH:49][CH:48]=2)=O)[CH:42]=[CH:41][C:40]=1[CH3:55].O>O1CCCC1>[CH:12]1(/[CH:17]=[C:45](\[C:43]2[N:44]=[C:39]([O:38][CH3:37])[C:40]([CH3:55])=[CH:41][CH:42]=2)/[C:47]2[CH:52]=[CH:51][C:50]([S:53][CH3:54])=[CH:49][CH:48]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1nc(C(=O)c2ccc(SC)cc2)ccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(/C(=C\C2CCCC2)c2ccc(SC)cc2)ccc1C
Yield: 40 %

Procedure:
A solution of lithiumhexamethyldisilazide in tetrahydrofuran (1 M, 5.5 mL) was added to a solution of (cyclopentylmethyl)triphenylphosphonium iodide (1.73 g, 3.66 mmol) in tetrahydrofuran (5 mL) in a nitrogen atmosphere under ice-cooling, and the mixture was stirred under ice-cooling for one hour. A solution of (6-methoxy-5-methylpyridin-2-yl)[4-(methylsulfanyl)phenyl]methanone obtained in Reference Example 1-36 (1.0 g) in tetrahydrofuran (2.5 mL) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:hexane=1:9→1:2) to give (Z)-6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-2-methoxy-3-methylpyridine (493 mg, 40%) as a more polar product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=[CH:10][N:9]([Si](C)(C)C)[CH:8]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][N:22]([CH3:26])[C:23]([N:9]1[CH:10]=[CH:11][C@H:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:8]1)=[O:24]
Reactant: CN(C)C(=O)Cl
Reactant: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)N1C=C[C@H]([Si](C)(C)C)C(C2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
To a stirred solution of 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine i (0.2 mL, 1.36 mmol) in CH2Cl2 (6 mL) under Ar was added dropwise dimethylcarbamyl chloride (0.19 mL, 2.04 mmol). The reaction mixture was stirred at RT for 1 day. It was then poured into a saturated solution of NaHCO3 (3 mL). The aqueous phase was extracted with CH2Cl2 (5 times). The combined organic layers were washed with water and brine and dried over MgSO4. Evaporation of the solvent under reduced pressure afforded 0.49 g of crude material that was purified by RPLC (silica gel, 5% EtOAc/hex) to give 59% (0.2506 g) of 3-(1-methylpyrrolidin-2-yl)-4-trimethylsilanyl-4H-pyridine-1-carboxylic acid dimethylamide iii as a clear oil. IR (thin film, neat, NaCl): 3363, 2924, 2348, 1657, 1449, 1377 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.65 (d, 1H, J=6.9 Hz), 6.35 (s 1H), 4.83-4.78 (m, 1H), 3.14-3.09 (m, 1H), 2.88 (s, 6H), 2.80-1.25 (m, 13H), 0.085 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 149.29, 147.15, 128.04, 124.49, 120.09, 106.29, 68.23, 57.35, 41.47, 38.53, 33.04, 30.34, 29.91, 22.37, 0.63, −2.00. HRMS Calcd for C16H29N3OSi: 308.2157 [M+H]+. Found: 308.2157 [M+H]+. [α]25D −15.17 (CH2Cl2, c=0.145).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:13]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:18]([O-:20])=[O:19].[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:13]=[C:12]([S:14](=[O:16])(=[O:15])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:22])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)cc(C(=O)OC)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1cc(C(=O)OC)c([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Solid dimethyl-2-nitro-5-chlorosulfonylisophthalate (2.78 g.) is added in portions to a stirred solution of 2.5 g. of N-methyloctadecylamine and 1.0 g. of triethylamine in 50 ml. of tetrahydrofuran. After the addition the reaction is stirred at room temperature for 30 min. The precipitated amine hydrochloride is removed by filtration and the filtrate concentrated under reduced pressure. The residue is recrystallized from acetonitrile, giving 2.7 g. of product, m.p. 70°-72° C. Additional material is obtained by concentration of the mother liquor.