Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([O:25]CCC#N)=[O:24])=[C:5]([O:30][C:31]([F:34])([F:33])[F:32])[CH:4]=1)#[N:2].[OH-].[Na+].C(OCC)C.O>COCCOC.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([OH:25])=[O:24])=[C:5]([O:30][C:31]([F:32])([F:33])[F:34])[CH:4]=1)#[N:2]
Reactant: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(=O)OCCC#N)=C(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1400 mg (2.96 mmol) of the compound from Example 36A are dissolved in 35 ml of 1,2-dimethoxyethane/water (2.5:1 v/v), 5.93 ml (5.93 mmol) of 1 N sodium hydroxide solution are added, and the mixture is stirred at room temperature for 2 h. The reaction mixture is then mixed with 50 ml of diethyl ether and 50 ml of water. The aqueous phase is separated off and adjusted to a pH of 4-5 with 1 N hydrochloric acid. The resulting suspension is then stirred for 1 h. The resulting precipitate is filtered off and washed with water and a little diethyl ether. Drying in vacuo results in 850 mg (68% of theory) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)([O-])=O.Cl.O.[OH-].[Na+]>CO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCC2
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a solution of 6-nitrotetralin (11.5 g, 64.9 mmol) in a mixture of methanol (30 mL) and conc. HCl (40 mL) was added iron powder (11.35 g, 203.2 mmol) by portions over 1 h at room temperature. The mixture was stirred for 1 h at room temperature, poured into water (600 mL), neutralized to ca. pH 6 by addition of 1N aqueous sodium hydroxide, extracted with ethyl acetate (300 mL×2). Organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give 9.45 g of the title compound: 1H NMR (CDCl3) δ6.85 (d, 1H, J=8.1 Hz), 6.46 (dd, 1H, J=8.1, 2.5 Hz), 6.42 (s, 1H), 3.44 (bs, 2H), 2.65 (m, 4H), 1.75 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ccc(Cl)cc2)nc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 6-(4-chloro-phenyl)-pyridin-3-ol (Preparation 23) and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a pale yellow solid (128 mg, 53.6%)
Reaction SMILES: C([N:4]1[C:12]([Cl:13])=[C:11]2[C:7](=[N:8][CH:9]=[N:10]2)[N:6]=[C:5]1[NH:14][C:15](=[O:17])[CH3:16])(=O)C.C(O[CH2:22][O:23][CH:24]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=O)C.C(S(O)(=O)=O)C>ClCCl>[C:32]([O:31][CH2:30][CH:24]([O:23][CH2:22][N:8]1[CH:9]=[N:10][C:11]2[C:7]1=[N:6][C:5]([NH:14][C:15](=[O:17])[CH3:16])=[N:4][C:12]=2[Cl:13])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:34])[CH3:33]
Reactant: CC(=O)Nc1nc2ncnc-2c(Cl)n1C(C)=O
Reactant: CC(=O)OCOC(COC(C)=O)COC(C)=O
Agent: CCS(=O)(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1nc(Cl)c2ncn(COC(COC(C)=O)COC(C)=O)c2n1
Yield: 23.7 %

Procedure:
A round-bottomed flask (10 ml) was charged with N-acetyl-2-acetamido-6-chloropurine (2.0 g, 7.9 mmoles), 1,3-diacetoxy-2-propoxymethyl acetate (2.7 g, 10.9 mmoles), and ethanesulfonic acid (63 mg). The mixture was heated in an oil bath maintained at 130° and a vacuum was applied. Thin layer chromatography showed no heterocyclic starting material after 1.5 hours and heating was discontinued. The mixture was dissolved in dichloromethane (50 ml) and filtered through Celite. The filtrate was evaporated to a residue and chromatographed on silica gel using dichloromethane/methanol (98:2) as the eluant. The product-containing fractions were combined and evaporated to give 0.75 g of pure product, m.p. 139°-140°.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]#[N:5].C[O:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15]>C1COCC1>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8](=[O:7])[CH2:3][C:4]#[N:5]
Reactant: COC(=O)c1ccccc1Br
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccccc1Br
Temperature: 0 °C
Yield: 59 %

Procedure:
To a suspension of NaH (60% dispersion, 1.14 g, 28.4 mmol) in dry THF (50 mL) under N2 was added CH3CN followed by 2-bromo-benzoic acid methyl ester (2 mL, 14.2 mmol). The reaction mixture was refluxed for 1.5 hour, then cooled to 0° C., quenched with water (1 mL), and concentrated in vacuo. The residue was diluted with water and the aqueous layer was extracted with hexane (2×), then acidified to pH 3-4 with 1N aqueous HCl. The milky aqueous layer was extracted with CHCl3 (3×), the combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification on silica gel with 0-35% EtOAc in hexane as eluent provided 1.89 g (59 % yield) of 3-(2-bromo-phenyl)-3-oxo-propionitrile as a yellow oil. 1H-NMR (d6-DMSO) δ: 11.8 (broad m, 1H, tautomers), 7.73 (broad s, 1H), 7.42 (m, 3H), 4.99 (s, 0.3H, tautomer), 4.64 (s, 0.6H, tautomer); HPLC/MS m/z: 223.9, 225.9 [MH]+.
Reaction SMILES: [C:1]([N:5]([C:14]1[CH:33]=[CH:32][C:17]([C:18]([NH:20][C:21]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]3[C:22]=2[CH:23]=[CH:24][CH:25]=[N:26]3)=[O:19])=[CH:16][CH:15]=1)[O:6][Si](C(C)(C)C)(C)C)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[C:1]([N:5]([C:14]1[CH:33]=[CH:32][C:17]([C:18]([NH:20][C:21]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]3[C:22]=2[CH:23]=[CH:24][CH:25]=[N:26]3)=[O:19])=[CH:16][CH:15]=1)[OH:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(O[Si](C)(C)C(C)(C)C)c1ccc(C(=O)Nc2ccc(O)c3ncccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)N(O)c1ccc(C(=O)Nc2ccc(O)c3ncccc23)cc1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 0.04 g (0.085 mmol) of compound 9 in THF (1 mL) was added 0.43 mL (0.43 mmol) of 1 M solution of tetrabutylammonium fluoride in THF at room temperature, and the solution was stirred for 1 hour. After completion of the reaction, 2 mL of water was added to quench the reaction. Ethyl acetate and sat'd NH4Cl solution were added to the mixture. The organic layer was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, Hex:EtOAc=10:1) to give 0.021 g of compound 10 in 70% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>CC(O)C.Cl.[NH4+].[Cl-].CS(C)=O>[C:17]([O:16][C:15](=[O:21])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCCCNc1cc(Cl)ncn1
Temperature: 100 °C
Yield: 41 %

Procedure:
4,6-Dichloropyrimidine (4.14 mmol) and tert-butyl 4-aminobutylcarbamate (4.14 mmol) were dissolved in 13 ml of 2-propanol, and 3 drops of 3M aq. HCl were added. The mixture was heated in a Personal Chemistry Optimizer microwave system at 100° C. for 900 s. The reaction mixture was diluted with sat. aq. NH4Cl-solution (50 ml) and extracted with EtOAc (2×). Drying of the organic layer (Na2SO4) and evaporation of the solvent under reduced pressure yielded the crude product, which was taken up in DMSO (2.5 ml) and purified via prep.-HPLC (XTerra Prep. MS C18 5 μm, 19×150 mm, gradient from water to MeCN over 14 min), yielding 41% of a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:22]([NH2:24])=O)[C:19]([NH2:21])=O.O.[OH-].[Na+]>C1COCC1>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH2:19][NH2:21])[CH2:22][NH2:24]
Reactant: NC(=O)C(CCCCOC1CCCCO1)C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC(CN)CCCCOC1CCCCO1
Temperature: 0 °C

Procedure:
6.8 g (0.18 mol) of lithium aluminium hydride were added with exclusion of moisture to 400 ml of absolute THF in a 1000-ml round-bottomed flask with reflux condenser and dropping funnel. Next, 15.5 g (0.06 mol) of the substituted malonic acid amide [18] in 100 ml absolute THF was slowly added dropwise and reflux-heated for 4 hours, then cooled to 0° C. 8 ml of water was carefully added followed by 6 ml of 20% caustic soda solution and a further 30 ml of water. The mixture was filtered and the remaining precipitate was twice extracted by boiling with THF. The combined filtrates were washed with saturated common-salt solution and dried over sodium sulphate. The solvent was removed in the rotary evaporator and the residue was distilled in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([CH3:22])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:19][C:17]1[CH:18]=[C:2]([CH3:1])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=2)=[C:15]([CH3:22])[CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-nitro-phenoxy)-2-isopropyl-phenol (478 mg, 1.59 mmol) in a mixture of ethanol (10 mL) and EtOAc (30 mL) was added catalyst (10% Pd/C, 100 mg). The mixture was hydrogenated under 50 psi at RT for 2h. The mixture was filtered through Celite® and concentrated to give the title compound of Step C (458 mg) as a brown solid. The title product of Step C was used without further purification in the next step. MS (APCl−) Calc.: 271.2. Found: 270.2 (M−1).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[C:26]([F:37])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:38])[CH:10]=1)(=[O:5])=[O:4])[CH3:2].C(O)(=O)C.O.S(=O)(=O)(O)O>C(OCC)(=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([F:37])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:38])[CH:10]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCCS(=O)(=O)CC)cc3C)c2)cc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
A mixture of ethyl 3-[4-({4′-[2-(ethylsulfonyl)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2-fluorophenyl]propanoate (0.19 g, 0.35 mmol), acetic acid (4.5 mL), water (4.0 mL) and conc. sulfuric acid (0.65 mL) was stirred at 90° C. for 4 hrs. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-ethyl acetate) to give the title compound (0.12 g, yield 61%) as colorless crystals.
Reaction SMILES: CC(OC([NH:8][C@@H:9]([CH2:14][CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:25]1([CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[CH2:15][CH2:14][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[N:8]=3)=[CH:18][CH:19]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3)cc2)=N1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
To a solution of methyl(2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-oxo-5-{4-[(phenylmethyl)oxy]phenyl}pentanoate (323 mg, 0.75 mmol) in dry DCM (4 ml) at 0° C., under nitrogen atmosphere was added trifluoroacetic acid (1 ml) dropwise. The resulting pale pink solution was allowed to warm to room temperature over 1 hour, then it was evaporated under reduced pressure, affording the title compound (D7, 291 mg, 0.68 mmol, 91%) as a greenish oil which may be used in the next step without any further purification; Rt (HPLC): 3.69 min; MS: (ES/+) m/z: 310 [MH+], C19H19NO3 requires 309.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C:15]([OH:18])([CH3:17])[CH3:16])[C:9]1=[O:19])=[C:5]([CH3:7])[CH3:6].[CH2:21]([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.S(OC)(OC)(=O)=O>O1CCCC1.C(O)(=O)C>[CH3:21][O:18][C:15]([C@@H:10]1[C@@H:11]([CH2:12][CH:13]=[CH2:14])[N:8]([C:4](=[C:5]([CH3:7])[CH3:6])[C:3]([O:2][CH3:1])=[O:20])[C:9]1=[O:19])([CH3:17])[CH3:16]
Reactant: C=CC[C@@H]1[C@@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: [Li]CCCC
Solvent: CC(=O)O
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@H](C(C)(C)OC)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl-2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (2.41 g) in tetrahydrofuran (72.3 ml) was added dropwise a solution of n-butyl lithium (5.41 ml of 1.74M solution in hexane) at -78° C. After stirring for 10 minutes at the same temperature, hexamethylphosphoric triamide (1.64 ml) was added thereto. The resultant solution was stirred for 15 minutes at -78° C. and a solution of dimethyl sulfate (1.62 ml) in tetrahydrofuran (14.6 ml) was added. The mixture was allowed to warm to ambient temperature over a period of 1.5 hours and stirred at ambient temperature overnight. Acetic acid (0.539 ml) was added to the mixture and the solvent was removed by distillation. The residue was dissolved in ethyl acetate (240 ml), and washed with a mixture of 10% aqueous sodium bicarbonate (10 ml) and a saturated aqueous sodium chloride. The aqueous washings were extracted with ethyl acetate and the combined extracts were washed with a saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate solution was filtered and evaporated in vacuo. The residue was chromatographed on silica gel (100 g) eluting with a mixture of ethyl acetate and methylene chloride (1:100 to 1:1) to give methyl 2-[(3S,4R)-3-(1-methoxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (1.66 g) as an oil.
Reaction SMILES: [CH2:1]([O:7][C:8]([C:10]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]([C:25]([OH:27])=[O:26])=[C:13]([CH3:28])[NH:12][C:11]=1[CH3:29])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].[C:30](O)([CH3:33])([CH3:32])[CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:22]([C:18]1[CH:17]=[C:16]([CH:15]2[C:10]([C:8]([O:7][CH2:1][CH:2]=[CH:3][CH:4]=[CH:5][CH3:6])=[O:9])=[C:11]([CH3:29])[NH:12][C:13]([CH3:28])=[C:14]2[C:25]([O:27][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)O
Reactant: CC=CC=CCOC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CC=CC=CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 73.1 %

Procedure:
199 mg (0.5 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (2,4-hexadienyl) ester, 44 mg (0.6 mM) of tert-butanol, 113 mg (0.55 mM) of dicyclohexylcarbodiimide and 61 mg (0.5 mM) of 4-dimethylaminopyridine were dissolved in 5 ml of dichloroethane, and refluxed for 2 hours. After the reaction mixture was chilled, insoluble matters were filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silicas gel column chromatography to obtain 198 mg of a crude material. This material was recrystallized with methanol, and 166 mg of tert-butyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained (yield 73%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[NH:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1.CCN(C(C)C)C(C)C.CS(C)=O>O.C(#N)C>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: OC1CNC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(N2CC(O)C2)nc1
Reaction time: 1 h
Yield: 105.2 %

Procedure:
2-chloro-5-nitro-pyrimidine (100 mg, 0.63 mmol), azetidin-3-ol hydrochloride (137 mg, 1.25 mmol), DIPEA (0.44 mL, 2.51 mmol) and DMSO (2 mL) were combined and stirred at it for 1 hr. The reaction mixture was partitioned with brine (50 mL) and THF (50 mL). The organic (THF) layer was separated, and the aqueous layer was extracted with a further portion of THF (50 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give an oil. The oil was taken up in a mixture of water and acetonitrile and freeze-dried to give (i) as a light yellow solid (130 mg). 1H NMR (400 MHz, Acetone) δ 9.03 (s, 2H), 4.91-4.64 (m, 1H), 4.49 (ddd, J=10.5, 6.6, 1.7 Hz, 2H), 4.04 (ddd, J=10.4, 4.3, 1.7 Hz, 2H).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:37])[C:35]=1[F:36])[CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][C:30]1[CH:33]=[C:34]([F:37])[C:35]([F:36])=[C:28]([F:27])[CH:29]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1cc(F)c(F)c(F)c1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2cc(F)c(F)c(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 67.2 %

Procedure:
A mixture of intermediate 59 (0.5 g, 1.36 mmol), 3,4,5-trifluorobenzylamine (0.66 g, 4.0 mmol) and MeOH (0.2 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and the mixture is purified by chromatography on silica gel; gradient elution with heptane: EtOAc (70:30-50:50) gives 0.44 g of the product 83. 1H NMR (CDCl3) δ 7.59 (s, 1H), 7.20-7.05 (m, 2H), 7.05-6.90 (m, 8H), 6.80-6.70 (m, 2H), 5.45-5.30 (m, 2H), 4.70-4.50 (m, 2H), 1.16 (s, 9H); MS: m/z 482 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.C(N(CC)C(C)C)(C)C.[Cl:34][CH2:35][C:36](Cl)=[O:37].O>C(Cl)Cl>[Cl:34][CH2:35][C:36]([N:22]1[CH2:23][CH2:24][CH:19]([C:16]2[S:17][CH:18]=[C:14]([C:11]3[CH2:10][CH:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[O:13][N:12]=3)[N:15]=2)[CH2:20][CH2:21]1)=[O:37]
Reactant: O=C(Cl)CCl
Reactant: Fc1cccc(F)c1C1CC(c2csc(C3CCNCC3)n2)=NO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]piperidine (i.e. the product of Example 1, Step D) (4.2 g, 12.0 mmol) and N,N-diisopropylethylamine (1.63 g, 12.6 mmol) in methylene chloride (25 mL) at 0° C. was added a solution of 2-chloroacetyl chloride (1.43 g, 1.26 mmol) in dichloromethane (3 mL), after which time the reaction mixture was allowed to warm to room temperature. After 4 h, the reaction mixture was poured into water and the layers were separated. The organic layer was washed with aqueous hydrochloric acid solution (1 N), saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography on silica gel (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a tan solid (2.8 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2N=CC=CC=2N=N1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>ClCCl.O>[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][N:50]([C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
4-Fluorobenzoic acid (6b) (7 g, 50 mmol) was dissolved in dichloromethane (100 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (10.5 g, 55 mmol), triethylamine (7.7 mL, 55 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (7.5 g, 55 mmol) were added successively, stirred for half an hour at room temperature, and then 1-tertbutoxycarbonylpiperazine (6a) (10.2 g, 55 mmol) was added and stirred overnight. On the next day, water was added to quench the reaction. The reaction solution was washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, the organic phases were concentrated to give 1-tertbutoxycarbonyl-4-(4-fluorobenzoyl)piperazine (6c), 14.8 g white solid (yield 96%). ESI-MS m/z calculated for: 308.15. found: 309.25 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C:13]3[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1
Reactant: COc1ccc2c(c1)-c1c(nc(NC(=O)C(C)(C)C)[nH]c1=O)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1ccc2ccc3nc(NC(=O)C(C)(C)C)[nH]c(=O)c3c2c1
Yield: 97.4 %

Procedure:
A mixture of N-(1,2,5,6-tetrahydro-9-methoxy-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.93 g, 2.84 mmoles) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.8 g, 3.5 moles) in dry benzene (60 ml) was refluxed under a nitrogen atmosphere for 3 hours. After cooling, benzene was removed under reduced pressure and the residue was purified on a silica gel column eluting with chloroform to give N-(1,2-dihydro-9-methoxy-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.9 g).