Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:22])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:23](N1C=CN=C1)([N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)=[S:24].O>CN(C)C1C=CN=CC=1.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([O:22][C:23]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[S:24])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(C(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(OC(=S)n2ccnc2)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Yield: 47 %

Procedure:
Tert-butyl (2S)-2-[(3-fluoro-4-methylphenyl)(hydroxy)methyl]pyrrolidine-1-carboxylate (1.30 g, 4.19 mmol), which had been obtained in Example 1 (1b), 1,1′-thiocarbonyldiimidazole (1.12 g, 6.28 mmol), and 4-(dimethylamino)pyridine (0.05 g, 0.42 mmol) were dissolved in tetrahydrofuran (8.4 mL) and stirred with heating under reflux for 16 hours. The reaction solution was cooled to room temperature. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL×3). After that, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to give the title compound as a yellow wax like substance (0.83 g, yield 47%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH:13]=[C:14]([N:18]=[N+]=[N-])[C:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.O[CH2:24]COCCOCCOC(C1C=CC=CC=1)=C(N=[N+]=[N-])C([O-])=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[C:21]2[C:12]([CH:13]=[C:14]([C:15]([O:17][CH3:24])=[O:16])[NH:18]2)=[CH:11][CH:10]=1
Reactant: COCCOCCOc1ccc(C=C(N=[N+]=[N-])C(=O)[O-])cc1
Reactant: [N-]=[N+]=NC(C(=O)[O-])=C(OCCOCCOCCO)c1ccccc1
Product: COCCOCCOc1ccc2cc(C(=O)OC)[nH]c2c1

Procedure:
Following the general procedure of EXAMPLE 3, and making non-critical variations but substituting 4-(2-(2-methoxyethoxy)ethoxy)-α-azidocinnamate (PREPARATION 79) for 4-[(2-(2-hydroxyethoxy)ethoxy)ethoxyl-α-azidocinnamate, the title compound is obtained, NMR (300 MHz, CD3OD) 7.59, 7.20, 7.02, 6.87, 4.25, 4.00, 3.96, 3.80, 3.67 and 3.47.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:32])[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C=O)C>[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:32])[C:27]([NH:1][CH:2]([C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(NC(COCc1ccccc1)C(=O)O)OCCCNc1ccccn1
Reactant: CCOC(=O)CC(N)c1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)C(COCc1ccccc1)NC(=O)OCCCNc1ccccn1)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
119.44 mg of ethyl 3-amino-3-(3,5-dichlorophenyl)propionate, 0.164 g of 3-benzyloxy-2-[3-(pyridin-2-ylamino)propoxycarbonylamino]propionic acid, 10.00 ml of DMF, 0.084 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.097 ml of 4-methylmorpholine are reacted together with stirring firstly for 1.5 hours at 50° C. and subsequently overnight at room temperature. After removal of the DMF by distillation, the residue is taken up in ethyl acetate, washed with water, evaporated to dryness and purified by chromatography over a short silica column (eluent ethyl acetate), giving ethyl 3-{3-benzyloxy-2-[3-(pyridin-2-ylamino)propoxycarbonylamino]propanoylamino}-3-(3,5-dichlorophenyl)propionate, RT 1.552 min, FAB-MS (M+H)+ 618.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](O)=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([Cl:26])=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1

Procedure:
To a solution of 7-((3-chlorobenzyl)oxy)quinoline-3-carboxylic acid (Example 46, product from Step A, 50 mg, 0.16 mmol) in DCM (1.5 mL) was added oxalyl chloride (0.1 mL, 1.13 mmol), followed by 1 drop of DMF. After 30 minutes the reaction was concentrated under reduced pressure to afford a yellow foam, and further dried under high vacuum for 15 minutes to afford the title compound, which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[CH:9][C:8]2=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].CO.Cl.[C:26](=O)([O:30]CC)[O:27]CC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:26]([OH:30])=[O:27])=[CH:9][C:8]2=[O:18])=[CH:19][CH:20]=1
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Yield: 15 %

Procedure:
A solution of 1-(4-chlorobenzyl)-1,2-dihydro-4-methyl-2-oxoquinoline (18.0 g.) in diethyl carbonate (80 ml.) was added to a stirred suspension of sodium hydride (15.4 g.; weighed as a 60% w/w dispersion in oil, but subsequently washed by decantation with light petroleum, b.p. 40°-60° C., to remove the oil) in diethyl carbonate (20 ml.). The mixture was stirred under reflux for 11/2 hours, and formed a thick suspension. This was cooled and treated with a small amount of methanol to destroy any remaining sodium hydride. Dilution with ether (400 ml.) gave a suspension from which the solid was filtered. This was suspended in ethanol (180 ml.) and brought to pH 3 by addition of hydrochloric acid. Water (600 ml.) was added, and the suspension was stirred for 30 minutes before the solid was collected by filtration, washed with water, and well drained. This solid [which comprised diethyl 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylmalonate] was dissolved in ethanol (180 ml.), to which was added aqueous 40% w/v sodium hydroxide (20 ml.), and the mixture was heated under reflux for 4 hours. The cooled mixture was added to water (600 ml.) to give a solution which was brought to pH 3 by addition of concentrated hydrochloric acid. The resultant precipitate was collected by filtration, washed with water, drained, and crystallised from ethanol to give 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylacetic acid, m.p. 208°-209° C., in 51% overall yield.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3Br)[CH2:5][C:4]=2[N:3]=1.NC1N=CC2C(=O)CC(C3C=CC(F)=CC=3[C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)CC=2N=1.N1C=CC(B(O)O)=CC=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:44]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=O
Reactant: Nc1ncc2c(n1)CC(c1ccccc1Br)CC2=O
Agent: OB(O)c1ccncc1
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1ccncc1)CC2=O

Procedure:
The title compound was prepared from 2-amino-7-(2-bromo-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/h stage 2), following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one using 4-pyridyl boronic acid instead of 3-pyridyl boronic acid.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].Br[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1.[Mg].[Cl-].[NH4+]>CCOCC.C1COCC1>[F:15][C:10]1[CH:9]=[C:8]([CH:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH:13]=[C:12]([F:14])[CH:11]=1
Reactant: CCCCC=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC(O)c1cc(F)cc(F)c1
Yield: 116 %

Procedure:
A solution of pentanal (19.0 g, 0.22 mol) in dry ether (75 ml) was added dropwise to a stirred solution of the Grignard reagent at room temperature, under dry nitrogen, prepared from 1-bromo-3,5-difluorobenzene (50.2 g, 0.26 mol) and magnesium (7.25 g, 0.30 mol) in dry THF (100 ml). The stirred mixture was heated under reflux for 2 h, cooled and a saturated solution of ammonium chloride (300 ml) was added. The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a pale-orange liquid (51.1 g) which was distilled to yield a colourless liquid. Smaller quantities of crude product were purified by column chromatography (silica gel/dichloromethane) to yield a colourless liquid (92%).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:20]C([N-]C(C)C)C.CI>C1COCC1>[CH3:20][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of O1-tert-butyl O4-ethyl piperidine-1,4-dicarboxylate (1.5 g, 5.84 mmol) in THF (25 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.80 M in THF, 6.5 mL, 11.68 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 45 min followed by addition of methyl iodide (1.2 mL, 17.52 mmol). The temperature was slowly raised up to RT and left at RT for 6 h. The reaction was cooled to 0° C. and quenched by the dropwise addition of saturated NH4Cl solution (50 mL). The reaction was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by chromatography on silica eluting with 2% EtOAc in hexane gave i (1.0 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:11].S(OC)(O[CH3:22])(=O)=O>C(=O)(O)[O-].[Na+]>[CH3:22][N:7]1[C:6](=[S:11])[N:5]2[C:4]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:3][C:2]([CH3:1])=[C:10]2[CH:9]=[N:8]1
Reactant: Cc1nc(-c2ccccc2)n2c(=S)[nH]ncc12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(-c2ccccc2)n2c(=S)n(C)ncc12
Reaction time: 15.5 h
Yield: 7 %

Procedure:
8-Methyl-6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-thione (3.76 g, 0.014 mole) is dissolved in aqueous sodium bicarbonate (125 ml. 6.7%). Dimethyl sulfate (1.85 g, 0.0147 mole) is added at room temperature and the reaction mixture stirred overnight (appr. 15-16 hours). The precipitated solid is collected by filtration and washed thoroughly with water. The dried solid (3.84 g) is extracted with benzene. The benzene solution is evaporated to dryness, and the residual red solid obtained is extracted with hexane. Evaporation of the hexane solution yields a tan solid (0.25 g). Recrystallization of this tan solid from methanol yields pale yellow crystals, m.p. 194°-195° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH3:15])[CH:8]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:2][C:1]([CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH3:15])[CH:8]=1)=[O:3])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(OCCC(=O)O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCC(=O)OCc2ccccc2)ccc1C=O
Reaction time: 8 h

Procedure:
To a suspension of 4-(2-carboxyethoxy)-2-methylbenzaldehyde (7.2 g) and potassium carbonate (14.3 g) in N,N-dimethylformamide (70 mL) was added benzyl bromide (8.2 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1) to give the title compound (6.47 g).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH:9]([C:11]([CH3:13])=[O:12])=[CH2:10].C(N)C.N1C=CN=C1>C(Cl)(Cl)Cl>[CH3:8][C:2]1[CH:1]=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:7][CH2:10][CH2:9][C:11](=[O:12])[CH3:13]
Reactant: C=CC(C)=O
Reactant: Cc1cccc(O)c1
Agent: CCN
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CC(=O)CCOc1cccc(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To m-Cresol (4.0 g, 37 mmol), methyl vinyl ketone (3.2 mL, 37 mmol) in chloroform (25 mL), was added diispropyl ethyl amine. The mixture was heated at reflux for 16 h, allowed to cool to room temperature and evaporated. The residue has 50% product and 50% starting material. The starting material was separated as t-butyldimethyl silyl ether. The product was isolated via plug filteration using silica gel 50% hexane/ethyl acetate. Yield 4.5 g (68%). As an alternative purification procedure, the crude reaction mixture was evaporated, dissolved in DMF (0.2M) and 0.5 equivalents of imidazole and 0.5 equivalents of tBDMSCI were added. The reaction was stirred for 3 hr at room temperature and then the solvents were removed in vacuo. To the residue was added 75 mL ethyl acetate and 75 mL water (ratio of 1/1). The ethyl acetate layer was separated and dried over Na2SO4. The solvents were removed in vacuo. The crude material was placed on a pad of silical gel and the silylated m-cresol was removed with hexanes. The product was obtained by eluting with 5-10% ethyl acetate in hexanes. The solvents were removed in vacuo to give the desired product. 1H(CDCl3):7.15 (t, 1H), 6.65-6.80(m, 2H), 4.25 (t, 2H), 2.75 (t, 2H), 2.25 and 2.35 (2 s, 3H each).
Reaction SMILES: O[CH2:2][C:3]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1.N1C=CC=CC=1.CS([Cl:26])(=O)=O>ClCCl>[Cl:26][CH2:2][C:3]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1
Reactant: COc1cc(C(C)C)ccc(CO)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc(CCl)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
7-hydroxymethyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one (2.81 g, 13.5 mmol) and pyridine (1.31 ml, 16.2 mmol) were dissolved in dichloromethane (5 ml) and cooled to 0° C. The solution was stirred while methanesulfonyl chloride (1.25 ml, 16.2 mmol) was added thereto. After stirred at 0° C. for 2 hours, the reaction solution was slowly brought back to room temperature. After 2 hours, the reaction solution was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate, water and 2N HCl, then dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [eluent:hexane/ethyl acetate (1:1)] to give 1.38 g of 7-chloromethyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one (yield: 45%) as a pale yellow oil. This oil was solidified when allowed to stand at room temperature.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:25])([CH3:26])[O:16][C:15]3=[O:27])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[Br:35]
Reactant: CC1(C)OC(=O)N(c2ccc(-c3ccc(N)nc3)cc2)[C@H]1c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)c(Br)c3)cc2)[C@H]1c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (S)-3-(4-(6-aminopyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (1 g, 2.78 mmol) in DCM (13.91 mL) at 0° C., was added NBS (0.545 g, 3.06 mmol). The reaction mixture was then stirred for 1 hour at the same temperature. LC-MS indicated clean and complete conversion to desired product. The solution was concentrated and water was added. The solid was filtered and washed with water three times. The solid was then air-dried affording (S)-3-(4-(6-amino-5-bromopyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (1.26 g, 2.87 mmol, 103% yield) as a tan solid. The material was used without further purification. m/z (ESI) 439.8 (M+2)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.[Br:10][C:11]1[N:16]=[C:15](Br)[C:14]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][N:12]=1>CCO>[Br:10][C:11]1[N:16]=[C:15]([NH:9][C:7]2[CH:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:5][N:6]=2)[C:14]([C:18]#[C:19][Si:20]([CH3:21])([CH3:23])[CH3:22])=[CH:13][N:12]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Br
Solvent: CCO
Product: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 12 h
Yield: 39.9 %

Procedure:
(Step 4) A solution of 3-cyclopropyl-1H-pyrazol-5-amine (12.241 g, 99.39 mmol, 1.5 equiv.) in EtOH was added to a solution of compound 2,4-dibromo-5-((trimethylsilyl)ethynyl) pyrimidine (22.136 g, 66.26 mmol,) in EtOH (220 mL) at 20° C. After 12 h, EtOH was evaporated under reduce pressure. The residue was purified by silica-gel column chromatography (mobile phase: petroleum ether/ethyl acetate=20/1˜5/1) to afford solid product 2-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine (9.948 g, 40%). LC-MS (m/z)=377.0 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCO)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)c1ccccc1
Yield: 98.8 %

Procedure:
Into a four-necked flask provided with a stirring means and a thermometer, 150 g (1 mol) of (+)-3-phenyl-1-butanol (XXVI-60), 500 ml of toluene and 200 ml of pyridine were charged, and 122.4 g (1.2 mol) of acetic acid anhydride and 1 g of 4-dimethylaminopyridine were further added thereto. The mixture was reacted for 4 hours while temperature being maintained at 40°-50° C. After completion of the reaction, the reaction mixture was poured into 500 ml of 4N hydrochloric acid, extracted and fractionated. The resulting organic layer was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate aqueous solution ad water in the order. The thus-obtained organic layer was concentrated under a reduced pressure to obtain 190 g of (+)-1-acetoxy-3-phenylbutane (XXV-60) with yield of 99.0%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1
Reactant: Cc1ncc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ncc(CO)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A solution of 2-methyl-pyrimidine-5-carbaldehyde (5 g, 41 mmol) in MeOH (100 mL) was added NaBH4 (2.3 g, 61.5 mmol) at 0° C. in portions and the resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to give the remains, which was suspended in H2O (20 mL) and extracted with EtOAc (5×50 ml). The organic layer was dried over Na2SO4 and concentrated to afford the title compound (2 g, yield: 39%). 1H NMR (CDCl3 400 MHz): δ8.64 (s, 2H), 4.72 (s, 2H), 2.73 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][C:16]=1[O:28][CH3:29]>C1COCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][C:24](=[CH:7][C:5]([O:4][CH3:3])=[O:6])[CH2:25][CH2:26]2)=[CH:17][C:16]=1[O:28][CH3:29]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1Cl
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=C1CCN(c2ccc(Cl)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A suspension of 60% dispersion sodium hydride (65.1 mg, 1.627 mmol) in anhydrous THF (2.5 mL) was treated with a solution of trimethyl phosphonoacetate (235 μL, 1.627 mmol) in THF (1 mL) over 5 min. The mixture was stirred at RT for 30 min and then treated with a solution of 1-(4-chloro-3-methoxyphenyl)piperidin-4-one (300 mg, 1.252 mmol) in THF (3 mL). The reaction was stirred at RT for 1 h before it was partitioned between saturated NH4Cl and EtOAc. The extract was dried (Na2SO4) and concentrated to give the crude product, which was purified by flash chromatography (12 g silica gel cartridge and gradient elution from 0 to 30% EtOAc/hexanes) to afford methyl 2-(1-(4-chloro-3-methoxyphenyl)piperidin-4-ylidene)acetate (288 mg, 0.974 mmol, 78% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.19 (1 H, d, J=8.79 Hz), 6.49 (1 H, d, J=2.42 Hz), 6.44 (1 H, dd, J=8.79, 2.64 Hz), 5.73 (1 H, s), 3.88 (3 H, s), 3.70 (3 H, s), 3.26-3.34 (4 H, m, J=5.82, 5.49, 5.33, 5.33 Hz), 3.10 (2 H, t, J=5.38 Hz), 2.45 (2 H, t, J=5.27 Hz).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]=[N:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1[OH:26])([O-])=O.ClC1C(=O)C2C(C(=[O:39])C=1Cl)=CC=CC=2.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>CO>[OH:26][C:16]1[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[N:14]1[N+:13]([O-:39])=[C:7]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]2=[N:3]1
Reactant: Cc1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
97% sodium hydroxide 9.6 g was added to methanol 100 ml, and was stirred at 65° C. for 30 minutes. After cooling to 50° C., 2-nitro-4-chloro-2'-hydroxy-3'-t-butyl-5'-methylazobenzene 11.6 g was added to the resultant mixture over 30 minutes, and thereafter 2,3-dichloro-1,4-naphthoquinone 0.7 g was added. Glucose 8 g was added to the resultant mixture at 40° to 45° C. over one hour, and the mixture was stirred for one hour at 40° to 45° C. As this result, almost all of the azobenzenes disappeared to produce 2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5-chlorobenzotriazole-N-oxide, thus the reaction of Process (b) being completed.