Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[C:17]([NH:19][CH2:20][C:21](=O)[CH3:22])=[O:18])=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.S(=O)(=O)(O)[OH:36].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[O:34]=[C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32](=[O:33])[N:24]1[CH:16]([C:17]1[O:18][C:21]([CH3:22])=[CH:20][N:19]=1)[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:1](=[O:36])[CH3:2])=[CH:10][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)CNC(=O)C(Cc1ccc(OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(CC(c2ncc(C)o2)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 57.5 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 3-(4-Benzyloxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-(2-oxo-propyl)-propionamide (5) (220 mg, 0.5 mmol) in acetic anhydride (2 mL) at room temperature was added concentrated sulfuric acid (0.2 mL). The mixture was stirred at 55-60° C. for 2 h, then sodium acetate (200 mg) was added, and the mixture was concentrated in vacuo. To the residue was added cold water (10 mL), the precipitated solid was collected, washed with water and dried, and the product was purified by flash chromatography on silica gel (20% ethyl acetate in DCM) to afford acetic acid 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(5-methyl-oxazol-2-yl)-ethyl]-phenyl ester (110 mg, 56%) as a light yellow solid; 1H NMR (CDCl3): □7.80 (m, 2H), 7.70 (m, 2H), 7.25 (d, 2H), 6.95 (d, 2H), 6.7 (s, 1H), 5.7 (m, 1H), 3.8 (m, 2H), 2.26 (s, 3H), 2.21 (s, 3H); LCMS m/z 391.1 (M+1).
Reaction SMILES: O=[CH:2][C:3]1[CH:12]=[CH:11][C:9]([OH:10])=[C:5](OCC)[CH:4]=1.[C:13](OC)(=O)C1C(=CC=CC=1)N>>[CH2:13]=[CH:4][CH2:5][CH:9]([OH:10])[CH2:11][CH2:12][CH2:3][CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: COC(=O)c1ccccc1N
Product: C=CCC(O)CCCC

Procedure:
The Schiff Base of Ethyl Vanillin and Methyl Anthranilate
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].C([Sn](CCCC)(CCCC)[C:42]([O:44][CH2:45][CH3:46])=[CH2:43])CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:45]([O:44][C:42]([C:2]1[C:18]([O:19][CH2:20][C@@H:21]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14])=[CH2:43])[CH3:46]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(Br)cc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 72 %

Procedure:
A solution of (S)-2-(1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (100 mg, 0.182 mmol), tributyl(1-ethoxyvinyl)stannane (132 mg, 0.365 mmol), DPPF (20.22 mg, 0.036 mmol) and Pd2(dba)3 (16.70 mg, 0.018 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen for 5 min then heated at 100° C. overnight. After cooling to ambient temperature, the volatiles were concentrated under reduced pressure. The residue was taken up in ethyl acetate and filtered through diatomaceous earth (Celite®). The organic filtrate was washed with H2O, then brine, dried over Na2SO4 and concentrated under reduced pressure to afford (S)-2-(1-((9-(1-ethoxyvinyl)-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (0.15 g, 0.131 mmol, 72% crude yield) as a black gummy solid. The material was carried forward without further purification. LC/MS (ESI) m/e 540.3 [(M+H)+, calcd for C32H34N3O5 540.2; LC/MS retention time (method G): tR=1.21 min.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[F:11][C:12]([F:16])([F:15])[CH2:13]I.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:11][C:12]([F:16])([F:15])[CH2:13][N:3]1[C:4](=[O:10])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[CH:2]1
Reactant: O=c1[nH]cnc2sccc12
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccsc2ncn1CC(F)(F)F
Temperature: 100 °C
Yield: 70.3 %

Procedure:
A mixture of thieno[2,3-d]pyrimidin-4(3H)-one (25 g, 164 mmol), 1,1,1-trifluoro-2-iodoethane (32.4 ml, 329 mmol) and cesium carbonate (53.5 g, 164 mmol) in DMF (100 ml) was heated at 100° C. for 18 h in a round bottom flask. 1 L of water was added to the reaction mixture and was extracted with ethyl acetate (3×300 ml). The combined organic phase was washed with water (500 ml), followed by brine. The organic phase was dried over MgSO4, filtrated, then concentrated in vacuo. The residue was purified by flash chromatography (0-100% ethyl acetate/DCM) to obtain the title compound (27 g, 70%). LCMS RT=0.88 min, M+H+=235.1.
Reaction SMILES: [OH-].[K+].Cl[CH2:4][C:5]([C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:16])=[C:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1)=[O:6].Cl.CN1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>>[CH3:26][CH:25]([CH2:10][CH2:9][CH:8]=[C:7]([CH3:12])[CH3:5])[CH2:24][CH2:23][O:27][CH2:4][C:5]([C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:16])=[C:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1)=[O:6]
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Reactant: CN1CCCC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)=CCCC(C)CCOCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Reaction time: 16 h

Procedure:
To a solution of 4.69 g (30 mmol) of 3,7-dimethyl-oct-6-dien-1-ol and 4.21 g (75 mmol) of potassium hydroxide in 150 ml of N-methylpyrrolidone a solution of 3.82 g (15 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone in 75 ml of N-methylpyrrolidone is added dropwise at room temperature and under inert atmosphere. After the addition is completed stirring is continued for additional 16 hours. Then the reaction mixture is acidified with 1N HCl and extracted with ethyl acetate. The collected organic phases are washed with water and brine, dried and evaporated. Crystallization of the crude product from hexane gives 2.58 g of compound 109, m.p. 37-39° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][N:21]1[C:25]([NH2:26])=[CH:24][CH:23]=[N:22]1.CCOC(C)=O>C(O)(C)C>[CH3:20][N:21]1[C:25]([NH:26][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)=[CH:24][CH:23]=[N:22]1
Reactant: Cn1nccc1N
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cn1nccc1Nc1ncc2c(n1)CCN(C(=O)c1cccnc1)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 1-methyl-1H-pyrazol-5-amine (0.010 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 62.3% yield (0.019 g, 0.057 mmol).
Reaction SMILES: [O-]CC.[Na+].C([C:8]1[O:16][C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)(O)=O>C(O)C>[O:16]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: O=C(O)c1cc2ncccc2o1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: c1cnc2ccoc2c1

Procedure:
Reaction of 30 with ethyl bromoacetate in the presence of a non-nucleophilic base such as sodium hydride in a suitable organic solvent such as tetrahydrofuran gives a compound of formula 31. Treatment of 31 with base such as sodium ethoxide in ethanol, followed by thermolysis of the resulting 2-carboxyfuro[3,2-b]pyridine of formula 32 gives furo[3,2-b]pyridine of formula 33 ((see., Shiotani, S., and Moriata, H. J. Heterocyclic Chem., 23, 665 (1986))
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:20]1[CH:25]=[CH:24][C:23](/[C:26](/[CH3:33])=[CH:27]/[C:28](OCC)=[O:29])=[CH:22][CH:21]=1>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:20]1[CH:21]=[CH:22][C:23](/[C:26](/[CH3:33])=[CH:27]/[CH2:28][OH:29])=[CH:24][CH:25]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2cc(OC)ccc2OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: COc1ccc(OC)c(-c2ccc(/C(C)=C/CO)cc2)c1

Procedure:
The colourless gum (E)-3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-enoate by a procedure analogous to that described in example 52b.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]>[Pt](=O)=O.C1COCC1>[NH2:19][C:16]1[CH:17]=[CH:18][C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[C:11]([CH:15]=1)[C:12]([NH2:14])=[O:13]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1-c1cc2ccccc2s1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: NC(=O)c1cc(N)ccc1-c1cc2ccccc2s1

Procedure:
2-(1-Benzothien-2-yl)-5-nitrobenzamide (4.75 g) is introduced into THF (250 ml) and, after addition of platinum dioxide (0.57 g), hydrogenated at RT under atmospheric pressure overnight. The reaction mixture is filtered through kieselguhr and washed with THF, and the organic phase is concentrated. The residue is stirred with diethyl ether, and the crystals are filtered off with suction. They are washed with diethyl ether and a little DCM and dried. Yield 2.39 g (56% of theory).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:3]1.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25].N.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C.C(Cl)Cl.CO.C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:24]([C:20]4[S:19][CH:23]=[CH:22][CH:21]=4)=[NH:25])=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:3]1
Reactant: CN1CCC(N2CCCc3cc(N)ccc32)C1
Reactant: CSC(=N)c1cccs1
Agent: Cl
Agent: I
Agent: N
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(N2CCCc3cc(NC(=N)c4cccs4)ccc32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroquinolin-6-amine (80 mg, 0.35 mmol) in 8 mL ethanol was treated with methyl thiophene-2-carbimidothioate hydroiodide (197 mg, 0.69 mmol) and stirred overnight at room temperature. The mixture was diluted with CH2Cl2 (10 mL) and argon was bubbled through the solution for 20 minutes. The solution was partitioned between CH2Cl2 (100 mL) and 1N NaOH (20 mL). After extraction, the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a dark residue which was subjected to flash chromatography on silica gel using 2.5% MeOH/CH2Cl2 then 5% 2M NH3 in MeOH/CH2Cl2. A light brown solid was obtained. This compound was converted to the dihydrochloride salt (95 mg, 65.6%). 1H-NMR (DMSO-d6) δ 7.67 (d, J=3.3 Hz, 1H), 7.55 (d, J=5.1 Hz, 1H), 7.08-7.06 (m, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.55-6.50 (m, 2H), 6.29 (brs, 2H), 4.46-4.37 (m, 1H), 3.21-3.15 (m, 2H), 2.74-2.69 (m, 4H), 2.50-2.43 (m, 2H), 2.25 (s, 3H), 2.15-2.04 (m, 1H), 1.86-1.67 (m, 3H). MS (ESI): 341.2 (M+1). ESI-HRMS calculated for C19H25N4S (MH+): 341.1794, Observed: 341.1788.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH3:34]>CO>[NH2:34][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: CO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (200 mg, 0.39 mmol) in 7 N ammonia in MeOH (2 mL) the title compound was obtained as a white powder (0.16 g, 0.328 mmol, 84.2% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.68-7.72 (m, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.18-7.28 (m, 5H), 6.76 (s, 2H), 6.00 (d, J=5.1 Hz, 1H), 3.25-3.31 (m, 1H), 1.36 (d, J=7.0 Hz, 6H). MS (ESI): 488.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)OCC(C)C)[CH:5]=[CH:6][C:7]=1[I:8].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:27]([O:32][CH2:33][C@@H:34]1[O:36]C1)(=[O:31])CCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][C@H:33]([CH2:34][OH:36])[O:32][C:27]2=[O:31])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: CC(C)COC(=O)Nc1ccc(I)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of isobutyl 3-fluoro-4-iodophenylcarbamate (Org. Process Res. Dev. 2001, 5(1), 80-83, 5.00 g, 14.83 mmol) in dry tetrahydrofuran (59 mL) at −78° C. under nitrogen is treated with lithium hexamethyldisilazide (1.0M in tetrahydrofuran, 15.6 mL, 15.57 mmol) dropwise and stirred at −78° C. for 45 minutes. Then, (R)-glycidyl butyrate (2.21 mL, 15.57 mmol) is added dropwise, and the resulting mixture is stirred at −78° C. for 1 h and at ambient temperature for 2.75 days. The reaction mixture is then quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (20 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (25 mL), and the combined organic phase is washed with water (25 mL) and saline (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product mixture is then chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of methanol/methylene chloride (1/99-2/98), and those fractions with an Rf=0.25 by TLC (methanol/chloroform, 5/95) are pooled and concentrated to give the title compound, mp 116-117° C.; MS (ESI+) for C10H9FINO3 m/z 338 (M+H)+; [α]25D=−41 (c 0.98, DMSO).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][NH2:13]>O>[CH:1](=[N:13][CH2:12][CH:11]([O:14][CH3:15])[O:10][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: O=Cc1ccccc1
Solvent: O
Product: COC(CN=Cc1ccccc1)OC
Reaction time: 2.5 h
Yield: 52.9 %

Procedure:
To a three neck round bottom flask, equipped with a cold water condenser, 20 g of water and 21.2 g of benzaldehyde were added. The reactants were mixed using a magnetic stirrer at room temperature for 3 minutes. Aminoacetaldehyde dimethyl acetal (21 g) was added to the reaction flask in one portion, followed by vigorous stirring for 2.5 hours. The agitation was stopped and the reaction mixture was allowed to stand for at least 15 minutes. The lower aqueous layer was separated and discard. The upper layer was collected and washed with saturated sodium chloride solution. The organic layer was collected and dried over magnesium sulfate to give 20.4 g of product. 1H NMR (300 Hz, CDCl3, ppm): 8.26 (1H, s), 7.65 (2H, m), 7.40 (3H, m), 4.66 (1H, t, J=5.3 Hz), 3.77 (2H, d,d, J=5.3 Hz, J=1.5 Hz), 3.39 (6H, s).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].[CH2:30](I)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(O)CCC>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCI
Reactant: CCCCCCCCCCOc1ccc(-c2nc3cc(O)ccc3o2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCCCCCOc1ccc(-c2nc3cc(OCCCCCCCC)ccc3o2)cc1
Yield: 52.1 %

Procedure:
In a 20 ml-round-bottomed flask, 0.25 g (0.68 mM) of 2-(4-decyloxyphenyl)-5-hydroxybenzoxazole, 0.08 g (1.21 mM) of potassium hydroxide and 3 ml of butanol were placed and heated to provide a solution. To the solution, 0.18 ml (1.00 mM) of octyl iodide was added, followed by heat-refluxing for 5 hours and 40 minutes under stirring. After the reaction, the solvent in the reaction mixture was distilled off under reduced pressure. To the residue, ethyl acetate and water were added, followed by stirring at room temperature. The organic layer was successively washed with 2%-sodium thiosulfate aqueous solution and water, followed by drying with anhydrous sodium sulfate and reduced pressure distillation. The resultant residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (acetone-methanol) to obtain 0.17 g of 2-(4-decyloxyphenyl)-5-octyloxybenzoxazole (Yield: 52.1%). ##STR82##
Reaction SMILES: [C:1]([N:20]1[CH2:22][CH:21]1[CH2:23][OH:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:27]([O:24][CH2:23][CH:21]1[CH2:22][N:20]1[C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: c1ccc(COCC2CN2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of lithium aluminum hydride in diethyl ether (1 M, 15 mL, 15 mmol) under an atmosphere of nitrogen, a solution of methyl 1-trityl-2-aziridinecarboxylate (5.04 g, 14.7 mmol) in anhydrous ether (60 mL) was added over a period of 0.5 h. The resultant mixture was allowed to slowly warm up and stirred at room temperature for 1 hour. The resultant mixture was cooled back to 0° C. and treated successively with water (0.57 mL) over a period of 10 minutes, followed by addition of 15% aq NaOH (0.57 mL), and water (1.7 mL). The resultant suspension was filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated with a mixture of ether (40 mL) and hexane (200 mL) with cooling. The precipitate was collected by filtration to provide (1-tritylaziridin-2-yl)methanol as white solid. Without further purification, the alcohol (1.0 g, 3.17 mmol) was added portionwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.24 g, 6.0 mmol). To the resultant mixture, terta-n-butylammonium iodide (50 mg, 0.14 mmol) and benzyl bromide (0.65 g, 3.8 mmol) were added. The reaction mixture was stirred at room temperature overnight and treated with water (20 mL). The organic extract was diluted with ether, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 5% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[NH2:8].[O:19]1[C:23]2([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:22][C:21]([C:29](O)=O)=[N:20]1>>[Cl:1][C:2]1[C:7]2[NH:8][C:29]([C:21]3[CH2:22][C:23]4([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[O:19][N:20]=3)=[N:9][C:6]=2[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Reactant: Nc1c(Cl)cc(-c2ccccc2F)cc1[N+](=O)[O-]
Product: Fc1ccccc1-c1cc(Cl)c2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1

Procedure:
The title compound was prepared from 3-chloro-2′-fluoro-5-nitro-biphenyl-4-ylamine (as prepared in the previous step) and 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared in Example 1, step B) according to the procedures described in Example 16, steps B and C. 1H-NMR (400 MHz, d4-MeOH) δ: 7.64 (br. s., 1H), 7.52 (td, J=7.8, 1.8 Hz, 1H), 7.48 (s, 1H), 7.35-7.43 (m, 1H), 7.27 (td, J=7.5, 1.3 Hz, 1H), 7.21 (ddd, J=11.1, 8.2, 1.1 Hz, 1H), 1.71-1.88 (m, 6H), 1.48-1.66 (m, 4H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@H:27]([N:34]([C:42](=[O:44])[CH3:43])[C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)[CH2:26][C@@H:25]3[CH3:45])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[N:9][C:10]=1[CH3:11])=[O:5])C.C(O)C.[OH-].[Na+]>O1CCCC1>[C:42]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][N:7]3[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[N:9]=[CH:8]3)=[CH:17][CH:18]=2)=[O:23])[C@@H:25]([CH3:45])[CH2:26]1)(=[O:44])[CH3:43]
Reactant: CCOC(=O)c1c(C)ncn1CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCn3cnc(C)c3C(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was dissolved in DMF at room temperature and K2CO3 was added. 3-(3-Bromo-propyl)-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester (prepared from the dibromide and the corresponding imidazole with NaH in THF) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (2% MeOH/95% CH2Cl2 to 10% MeOH/90% CH2Cl2) to afford (2S,4R)-3-[3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester. The ester (0.080 g, 0.12 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature 16 hours. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give (2S,4R)-3-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-5-methyl-3H-imidazole-4-carboxylic acid in 61% yield.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:16]=[C:15]([F:17])[C:13](=[O:14])[NH:12][C:10]1=[O:11])(=O)C.[OH-].[Na+]>>[OH:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:16]=[C:15]([F:17])[C:13](=[O:14])[NH:12][C:10]1=[O:11]
Reactant: CC(=O)OCCOCn1cc(F)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(=O)n(COCCO)cc1F

Procedure:
N1 -acetoxyethoxymethyl-5-fluorouracil was reacted with 1N NaOH for 1 hour at 40° C. to obtain N1 -2-hydroxyethoxymethyl-5-fluorouracil.