Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([C:28]3[CH:29]=[CH:30][C:25]([CH3:34])=[CH:26][CH:27]=3)=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(-c2nncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc23)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.1 g, 296 μmol), p-tolyl boronic acid (40 mg, 296 μmol) and tetrakis(triphenylphosphine)palladium (17 mg, 15 μmol) in 5 mL DME/EtOH (4:1) was treated with 2 M potassium carbonate (444 μl, 888 μmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled to room temperature and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give title compound in (95 mg) as a pale yellow solid. Found MS (ES+): 394(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:19]#[N:20])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(c2ccc(Cl)cc2)CCCC1
Temperature: 130 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (320) (14 g, 48.48 mmol) in dimethyl sulfoxide (50 mL) were added KI (805 mg, 4.85 mmol) and NaCN (3.6 g, 72.72 mmol) and stirred for 130° C. for 4 h. After completion of reaction, cold water (200 mL) was added. After extraction with ethyl acetate (3×100 mL), the combined organic parts were washed with saturated ferrous sulphate solution (2×100 mL), water (2×100 mL) and brine (100 mL) and dried and concentrated. The crude product was purified by CombiFlash column (10-20% ethyl acetate in hexane was used as eluent) to get [1-(4-chlorophenyl)-cyclopentyl]-acetonitrile (321) (8.2 g, 77%) as a light yellow liquid.
Reaction SMILES: [C:1]12([N:6]3[C:10]4[N:11]=[C:12](Cl)[N:13]=[CH:14][C:9]=4[C:8]([C:16]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=4)=[O:17])=[CH:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]12([N:6]3[C:10]4[N:11]=[C:12]([NH:32][CH2:31][C:30]5[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[N:13]=[CH:14][C:9]=4[C:8]([C:16]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=4)=[O:17])=[CH:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: COc1ccc(CN)cc1
Reactant: O=C(c1cncc(Br)c1)c1cn(C23CC(C2)C3)c2nc(Cl)ncc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CNc2ncc3c(C(=O)c4cncc(Br)c4)cn(C45CC(C4)C5)c3n2)cc1
Temperature: 110 °C
Yield: 84 %

Procedure:
To a solution of (7-Bicyclo[1.1.1]pent-1-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-bromo-pyridin-3-yl)-methanone (Preparation 284, 1.1 g, 2.72 mmol) and 4-methoxy benzyl amine (1.06 mL, 8.16 mmol) in dioxane (40 mL), DIPEA (1.7 mL, 10.8 mmol) was added and mixture was heated at 110° C. under microwave irradiation for 6 hours. The volatiles were removed in vacuo and the residue was partitioned between water (50 mL) ethyl acetate (150 mL). Organic phase was dried over sodium sulphate, evaporated in vacuo and purified by column chromatography on silica gel (gradient of EA:Hexane 25:75) to afford the title compound as off white solid in 84% yield, 1.15 g.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20](O)=[O:21])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.C(Cl)(=O)C([Cl:28])=O>ClCCl.CN(C=O)C>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([Cl:28])=[O:21])=[CH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of 0.43 g (1.22 mmol) of 2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carboxylic acid in 8 ml of dichloromethane was treated at RT with 2 drops of DMF. 0.12 ml (1.34 mmol, 1.1 eq) of oxalyl chloride were added within 5 min and stirring was continued for 2 h. The solution was evaporated and dried under reduced pressure to give 0.45 g of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].N12CCN(CC1)CC2>>[CH3:18][O:17][C:13](=[O:16])[C:14](=[CH2:15])[CH:11]([OH:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)OC
Reactant: O=CCCCCc1ccccc1
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OC)C(O)CCCCc1ccccc1
Reaction time: 120 h

Procedure:
A mixture of 8.4 g (52 mmol) of 5-phenylpentanal, 8.95 g (104 mmol) of methyl acrylate and 200 mg of 1,4-diazabicyclo[2.2.2]octane is allowed to stand at room temperature for 120 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][C:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH2:19]>>[F:23][C:22]([F:25])([F:24])[C:21]([NH:20][CH2:17]/[CH:18]=[CH:19]/[C:2]1[CH:16]=[CH:15][CH:14]=[C:4]([CH2:5][CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:3]=1)=[O:26]
Reactant: OC1(CCc2cccc(Br)c2)CCCCC1
Reactant: C=CCNC(=O)C(F)(F)F
Product: O=C(NC/C=C/c1cccc(CCC2(O)CCCCC2)c1)C(F)(F)F

Procedure:
Coupling of 1-(3-bromophenethyl)cyclohexanol with N-allyl-2,2,2-trifluoroacetamide following the method described in Example 118 gives (E)-2,2,2-trifluoro-N-(3-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)allyl)acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:29].[K+].[K+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:29])=[CH:22][CH:21]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2nc(-c3cccc(C)c3)c(-c3ccnc(C)c3)s2)cc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(-c2nc(-c3ccc(S(C)=O)cc3)sc2-c2ccnc(C)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.5 %

Procedure:
To a solution of 4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-2-[4-(methylthio)phenyl]-1,3-thiazole (0.55 g, 1.4 mmol) in acetic acid (15 mL) was added a solution of potassium persulfate (0.43 g, 1.6 mmol) in water (8 mL), and the mixture was stirred for 14 hours at room temperature. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, then, the solvent was distilled off. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), hexane-ethyl acetate=1:4), and recrystallized from ethyl acetate-hexane to obtain a title compound (0.15 g, yield 26%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16](=O)[CH3:17])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]([C:7]1[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=2[C:16]=1[CH3:17])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1c(O)cccc1OCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12

Procedure:
The (2-acetyl-3-hydroxy-phenoxy)-acetic acid tert-butyl ester was dissolved in DMF, and heated to 110-130° C. in the presence of potassium carbonate for 4 hours. The resulting suspension was slowly poured into cold water. The product precipitated out and was collected by filtration. Recrystalyzation in toluene afforded 34.26 g of the desired 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as pale yellow solid (60% overall yield).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([O:34][CH3:35])=[CH:26][N:25]=4)[CH2:20][NH:19]3)=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:69]([O:73][C:74]([NH:76][CH:77]([C@H:81]([CH3:89])[CH2:82][CH:83]([CH3:88])[CH2:84][CH2:85][CH:86]=[CH2:87])[C:78](O)=[O:79])=[O:75])([CH3:72])([CH3:71])[CH3:70]>ClCCl>[CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([O:34][CH3:35])=[CH:26][N:25]=4)[CH2:20][N:19]3[C:78](=[O:79])[CH:77]([NH:76][C:74](=[O:75])[O:73][C:69]([CH3:72])([CH3:71])[CH3:70])[C@H:81]([CH3:89])[CH2:82][CH:83]([CH3:88])[CH2:84][CH2:85][CH:86]=[CH2:87])=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2ncc(OC)c3ccccc23)CN1)C(=O)NS(=O)(=O)C1CC1
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OC)c3ccccc23)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)—N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxamide (595 mg, 1.9 mmol) in dichloromethane (15 mL) was added HATU (755 mg, 1.9 mmol) followed by DIPEA (1.7 mL, 9.9 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoic acid (1.0 g, 1.9 mmole) was added to the reaction mass and the solution was stirred at room temperature for 30 min. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (70% ethyl acetate in pet ether) to get desired product tert-butyl ((3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate as a pale yellow solid. MS: MS m/z 782.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:16])=O)=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:14]([Cl:16])[C:13]2[CH:17]=[CH:18][C:10]([CH3:9])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(Cl)=Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(4-bromo-phenyl)-4-methyl-benzimidoyl chloride used is prepared by the following procedure. To a solution of 4-bromoaniline (29.2 mg, 0.17 mmol) and 4-methyl benzoyl chloride (22.5 μL, 0.17 mmol) in dichloromethane was added triethylamine (28 μL, 0.20 mmol). After stirred at room temperature for 30 minutes, the solvent was removed. The residue was added 0.5 mL of thionyl chloride. The reaction mixture was heated at 80° C. for 1 h, concentrated. The product was used in the next step reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.C([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=2)[CH:18]=[C:17]1B(O)O)(OC(C)(C)C)=O>>[Cl:25][C:22]1[CH:23]=[C:24]2[C:19]([CH:18]=[C:17]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)[NH:16]2)=[CH:20][CH:21]=1
Reactant: Cc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Product: Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1

Procedure:
3-Methyl-5-bromopyridine and N-Boc-6-chloro-indole-2-boronic acid are processed according to the procedure described in Example 91 to give 6-chloro-2-(5-methyl-pyridin-3-yl)-1H-indole. (ESI) m/z 243.0 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:21]1[O:23][CH2:22]1.O1CCOCC1>O1CCCC1>[OH:23][CH2:22][CH2:21][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]=1[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: C1CO1
Reactant: O=C(Nc1ccccc1)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1ccncc1CCO
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of N-phenylisonicotinamide (1.98 g, 10 mmol) in tetrahydrofuran (40 ml) at -78° C. was added a solution of n-butyllithium (1.6M in hexanes; 13.5 ml, 21.6 mmol) and the resulting red solution stirrred for 40 minutes before addition of a solution of ethylene oxide in dioxane (3.56M; 3.0 ml, 11 mmol). After allowing the mixture to warm to room temperature over 21/2 hours, the reaction was quenched by addition of methanol (8 ml). The solvent was evaporated and the residue partitioned between ethyl acetate (70 ml) and water (25 ml). The organic layer was washed with saturated brine (25 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica eluting with 10% methanol/dichloromethane to afford the title compound as a solid (1.05 g, 43%); δH (CDCl3) 3.07 (2H, t, J 5.6 Hz, ArCH2 CH2OH), 3.70 (1H, br s, OH), 4.10 (2H, t, J 5.6 Hz, ArCH2 CH2OH), 7.15-7.19 (1H, m, ArH), 7.35-7.39 (2H, m, ArH), 7.49 (1H, d, J 5.2 Hz, ArH), 7.69-7.71 (2H, m, ArH), 8.44-8.48 (2H, m, ArH), 9.77 (1H, s, NH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH3:21]I>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]=[C:9]1[N:13]([CH3:21])[CH:12]=[CH:11][S:10]1
Reactant: CI
Reactant: CCOC(=O)C(C)c1ccc(Nc2nccs2)c(F)c1
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(N=c2sccn2C)c(F)c1
Yield: 58.5 %

Procedure:
A mixture of ethyl 2-[3-fluoro-4-(N-thiazol-2-ylamino)phenyl]propionate (11.l g), methyl iodide (44.5 ml) and ethanol (44.5 ml) is heated at 50°-55° C for 48 hours. The resultant mixture is treated in the same manner as in Example (1) and (2) to give ethyl 2-[3-fluoro-4-(3-methyl-4-thiazolin -2-ylideneamino)phenyl]propionate (6.8 g). (Yield 58.5 %).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1

Procedure:
A solution of 1-fluoro-4-nitrobenzene (2.0 g, 1.50 mL, 14 mmol), piperidine-4-carboxylic acid ethyl ester (2.2 g, 2.15 mL, 14 mmol), and potassium carbonate (9.7 g, 70 mmol) in CH3CN (20 mL) was stirred at room temperature overnight. The resulting mixture was filtered and concentrated. The residue was purified by chromatography on silica gel (gradient elution with 5-50% ethyl acetate in hexanes) to produce 2.0 g of 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid ethyl ester as a yellow solid. 1.0 g of the above 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid ethyl ester was hydrogenated using 10% Pd/C (200 mg) in MeOH, under 50 psi pressure of hydrogen for 2 hours. The catalyst was filtered, and the residue was concentrated to produce 1-(4-amino-phenyl)-piperidine-4-carboxylic acid ethyl ester. This material was directly used in the next step without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[C:11]([O:12][CH2:13][C@@H:14]2[CH2:16][O:15]2)=[CH:10][CH:9]=[CH:8][N:7]=1.O.[N-]=[N+]=[N-].[Na+]>O.O1CCOCC1>[N:1]([CH2:16][C@H:14]([OH:15])[CH2:13][O:12][C:11]1[C:6]([Cl:5])=[N:7][CH:8]=[CH:9][CH:10]=1)=[N+:2]=[N-:3]
Reactant: Clc1ncccc1OC[C@@H]1CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=NC[C@H](O)COc1cccnc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
Dissolve sodium azide (22.84 g, 351.3 mmol) in water (195 mL). Separately, dissolve 2-chloro-3-[[(2S)-oxiran-2-yl]methoxy]pyridine (32.6 g, 175.6 mmol) in 1,4-dioxane (800 mL). Slowly add the water/sodium azide solution to the dioxane solution; heat to 90° C.; and stir for 1 hour. Cool the mixture and concentrate it under reduced pressure. Add water; extract with EtOAc (2×); combine the extracts; dry the combined extracts over Na2SO4; filter; and collect the filtrate. Remove the solvents under reduced pressure to provide the title compound (40.28 g, 92.8%) as a reddish white solid. MS (m/z): 229 (M+1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:18][C@H:17]([O:19][C:20](=[O:22])[CH3:21])[C@@H:16]([CH3:23])[O:15][C@:6]1([NH:24][C:25](=[O:35])[CH2:26][P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28])[O:7]CC1C=CC=CC=1)(=[O:3])[CH3:2].C(O)C>[Pd].C(O)=O>[C:1]([O:4][C@H:5]1[CH2:18][C@H:17]([O:19][C:20](=[O:22])[CH3:21])[C@@H:16]([CH3:23])[O:15][C:6]1([NH:24][C:25](=[O:35])[CH2:26][P:27]([O:29][CH2:30][CH3:31])([O:32][CH2:33][CH3:34])=[O:28])[OH:7])(=[O:3])[CH3:2]
Reactant: CCOP(=O)(CC(=O)N[C@]1(OCc2ccccc2)O[C@H](C)[C@@H](OC(C)=O)C[C@@H]1OC(C)=O)OCC
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: CCOP(=O)(CC(=O)NC1(O)O[C@H](C)[C@@H](OC(C)=O)C[C@@H]1OC(C)=O)OCC

Procedure:
Crude benzyl 2,4-di-O-acetyl-3,6-dideoxydiethylphosphonoacetamido-alpha-D-mannopyranoside, 21, ethanol (10 mL), 2 88% formic acid and 0.1 g Pd black were heated at reflux overnight under argon with stirring. The reaction mixture was filtered and evaporated to dryness, and the residue was chromatographed on SiO2 (40 g; dichloromethane-methanol 95:5) to afford 0.57 g 2,4-di-O-acetyl-3,6-dideoxydiethylphosphonoacetamido-D-mannopyranose, as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1([CH2:7][CH3:8])[CH2:6][CH2:5]1)=[O:3].[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([OH:11])=[O:10]>>[CH2:7]([C:4]1([C:2]([CH:1]=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=2)=[O:3])[CH2:6][CH2:5]1)[CH3:8]
Reactant: CCC1(C(C)=O)CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: CCC1(C(=O)C=Cc2ccc(C(=O)O)cc2)CC1

Procedure:
2-(4-Carboxyphenyl)vinyl 1-ethylcyclopropyl ketone [III; Ar is 4-HO2CC6H4, R is C2H4 ] was prepared from 67.2 g. of 1-ethylcyclopropyl methyl ketone and 90 g. of p-carboxybenzaldehyde according to the procedure described above in Preparation A1, affording 40 g., m.p. 183.5°-184.5° C. when recrystallized from acetonitrile and then repeatedly from isopropyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]#[N:31])=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Reactant: N#Cc1cccnc1Cl
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]phenyl)methanol (400 g) and then 2-chloro-3-cyanopyridine (206.7 g) were added to dimethylformamide (1.6 L). To the obtained mixture was added triturated sodium hydroxide (59.4 g) and the mixture was stirred at 20-30° C. for 48 hrs. Water (1.6 L) was dropwise added at the same temperature and the mixture was stirred for 2 hrs. The precipitated crystals were collected by filtration, washed with water (1.6 L) and then ice-cooled ethyl acetate (800 ml), and dried (40° C.) under reduced pressure to give 2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)nicotinonitrile as white crystals.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([OH:8])=[CH:3][C:4]([OH:7])=[CH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:20][C:21](Cl)=[O:22].O>[N+](C1C=CC=CC=1)([O-])=O>[OH:8][C:2]1[C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]2[C:21](=[O:22])[CH2:20][O:7][C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Oc1ccc(-c2ccccc2)c(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1COc2cc(O)c(-c3ccccc3)cc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
A solution of biphenyl-2,4-diol (0.24 g, 1.3 mmol) in nitrobenzene (1.0 mL) was added with aluminum chloride (0.60 g, 4.5 mmol) at room temperature. Then, the reaction mixture was added with chloroacetyl chloride (0.60 g, 1.7 mmol) under ice cooling. The mixture was stirred at 40° C. for 3 hours, and then added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (100:0→90:10)) to obtain 6-hydroxy-5-phenylbenzofuran-3(2H)-one (0.12 g, 42%).
Reaction SMILES: CS([C:5]1[N:6]=[N:7][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:9][N:10]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>O1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:33][O:32][C:28]1[CH:27]=[C:25]([NH:26][C:5]2[N:6]=[N:7][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:9][N:10]=2)[CH:24]=[C:23]([O:22][CH3:21])[C:29]=1[O:30][CH3:31]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(S(C)(=O)=O)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(C(C)NC(=O)OC(C)(C)C)nn2)cc(OC)c1OC
Reaction time: 24 h
Yield: 49.3 %

Procedure:
To a stirred solution of tert-butyl 1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethylcarbamate (Intermediate 7) (2.0 g, 6.5 mmol) in tetrahydrofuran (50 mL) was added 3,4,5-trimethoxyaniline (1.8 g, 9.7 mmol) and 4-toluenesulfonic acid monohydrate (60 mg). After stirring for 24 hours, silica gel (10 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (20:80) to ethyl acetate:hexanes (50:50) using a RediSep silica gel cartridge (40 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give tert-butyl 1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethylcarbamate (1.3 g) as a white solid. 1H NMR (CDCl3): δ8.30 (s, 1H), 7.49 (br, 1H), 6.95 (s, 2H), 5.40-5.30 (m, 1H), 5.00-4.83 (m, 1H), 3.89 (s, 6H), 3.84 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.43 (s, 9H). MS m/z 406 (M+1).