Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([OH:14])=O)=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:16]1([NH:15][C:12]([C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][NH:10][N:9]=2)=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1n[nH]cc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1n[nH]cc1-c1ccccc1
Yield: 28.5 %

Procedure:
A solution of 4-phenyl-1H-pyrazole-3-carboxylic acid (75 mg; 0.4 mmol) (prepared according to Example 228C), aniline (45 ml; 0.48 mmol), EDAC (92 mg; 0.48 mmol) and HOBt (65 mg; 0.48 mmol) in 5 ml of DMF was stirred at room temperature overnight. The reaction was evaporated then purified by flash column chromatography eluting with 1:3 then 1:2 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 30 mg of 4-phenyl-1H-pyrazole-3-carboxylic acid phenylamide as a white solid. (LC/MS: Rt 3.12 [M+H]+ 264).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].[C@H:15]12[CH2:21][C@H:18]([NH:19][CH2:20]1)[CH2:17][N:16]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CC([O-])(C)C.[K+].C([O-])(O)=O.[Na+]>CCOC(C)=O.O1CCOCC1>[NH2:10][C@H:8]([C:7]1[N:6]=[C:5]2[CH:11]=[CH:12][N:13]([CH3:14])[C:4]2=[CH:3][C:2]=1[N:19]1[CH2:20][C@@H:15]2[CH2:21][C@H:18]1[CH2:17][N:16]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:9]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 33.2 %

Procedure:
To a 50 mL pear flask were added (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (628 mg, 2.471 mmol) and (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (906 mg, 4.57 mmol). After evacuating the flask and flushing it with nitrogen, 1,4-dioxane (5.9 mL) and potassium 2-methylpropan-2-olate (1 M in THF, 5.4 mL, 5.4 mmol) were added. The mixture was heated to 90° C. for 1 hour. The reaction mixture was then cooled and worked up with saturated NaHCO3 and EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (acid mode, 25-65% ACN/water gradient). The product-containing fractions were combined, neutralized with a small amount of saturated NaHCO3, concentrated in vacuo to remove ACN, and then extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (305 mg, 33.2%). ESI-MS m/z [M+H]+ calc'd for C20H29N5O2, 372. found 372.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[NH2:19][NH2:20]>C(O)C>[F:14][C:13]([F:16])([F:15])[C:12]1[C:7]([O:6][CH2:5][C:4]([NH:19][NH2:20])=[O:3])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: NN
Reactant: CCOC(=O)COc1ncccc1C(F)(F)F
Solvent: O
Solvent: CCO
Product: NNC(=O)COc1ncccc1C(F)(F)F
Yield: 77 %

Procedure:
As described for example 112a, (3-trifluoromethyl-pyridin-2-yloxy)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 77%). MS: m/e=236.2 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1([CH3:14])[NH:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5].N[C@@H:16]([C:19](O)=[O:20])CS>>[CH3:1][CH2:2][O:3][C:4]([C:6]1([CH3:14])[N:10]([C:19](=[O:20])[CH3:16])[CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5]
Reactant: CCOC(=O)C1(C)NC(C(=O)O)CS1
Reactant: N[C@H](CS)C(=O)O
Product: CCOC(=O)C1(C)SCC(C(=O)O)N1C(C)=O

Procedure:
By a method similar to that in Synthetic Example 7 except for the use of 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester synthesized from D-cysteine by a method similar to that in Reference Example 2, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester was obtained (with the ratio of cis form:trans form of about 43:57 as confirmed by NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F-:13].[K+]>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([F:13])=[O:5]
Reactant: [F-]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Cl
Agent: [K+]
Product: O=C(F)c1cc(F)c(F)cc1Cl

Procedure:
Into a 200 cc glass reactor equipped with a reflux condenser, 50 g of 2-chloro-4,5-difluorobenzoylchloride, 13.7 g of spray dried potassium fluoride and 100 g of sulforane were charged and reacted at 135° C. for 4 hours under stirring. After cooling, the inorganic salts were filtered off, and the residue was subjected to distillation under reduced pressure to obtain 42 g of 2-chloro-4,5-difluorobenzoyl fluoride. The physical properties of the obtained 2-choloro 4,5-difluorobenzoyl fluoride were as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6].Br[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ncccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(OC)cccc1-c1ncccn1
Temperature: 80 °C
Yield: 63.4 %

Procedure:
In a microwave vial was dissolved methyl 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (500 mg, 1.71 mmol), commercially available from Combi-Blocks (CAS #1146214-77-8), and 2-bromopyrimidine (344 mg, 2.05 mmol) in THF (8.5 mL). Na2CO3 (544 mg, 5.14 mmol) was then added followed by water (4 mL) and the reaction mixture was degassed with N2 for 10 minutes. PdCl2(dtbpf) (45 mg, 0.069 mmol) was then added and the reaction mixture was heated at 80° C. for 4 h. The mixture was cooled to room temperature and water and EtOAc added. The reaction mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude was purified via silica gel chromatography (0-70% EtOAc in hexanes) to afford the title compound (265 mg, 63%). MS (ESI) mass calcd. for C13H12N2O3, 244.1; m/z found 245.1 [M+H]+. 1H NMR (400 MHz, Chloroform-d) 8.78 (d, J=4.9 Hz, 2H), 7.99 (dd, J=7.9, 0.9 Hz, 1H), 7.49 (t, J=8.1 Hz, 1H), 7.19 (t, J=4.8 Hz, 1H), 7.09 (dd, J=8.3, 0.9 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:14]2=[C:15]3[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][N:18]=1.Br[CH2:29][CH:30]1[CH2:32][CH2:31]1.[Cl-].[NH4+]>CN(C)C=O>[CH:32]1([CH2:31][N:16]([C:4]2[CH:3]=[C:14]3[C:15]4[CH:10]([CH2:11][CH2:12][CH2:13]3)[CH2:9][CH2:8][CH2:7][C:6]=4[CH:5]=2)[C:17]2[N:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4CCC3)nc1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(N(CC2CC2)c2cc3c4c(c2)CCCC4CCC3)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A suspension of sodium hydride (60%, 0.009 g) in N,N-dimethylformamide (2 ml) was added with ethyl 2-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]pyrimidine-5-carboxylate (0.035 g) dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with bromomethylcyclopropane (0.025 ml), and the mixture was stirred overnight. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, the resulting residue was suspended in ethanol (5 ml), the suspension was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:5) to obtain the title compound (0.039 g, yield: 96%) as pale yellow amorphous.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:25]([O-:27])=[O:26])[CH:8]=2)[N:3]=1.[CH2:28]([NH2:31])[CH:29]=[CH2:30]>O>[CH2:28]([NH:31][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:25]([O-:27])=[O:26])[CH:8]=2)[N:3]=1)[CH:29]=[CH2:30]
Reactant: CCCCCCCCCCCCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: C=CCN
Solvent: O
Product: C=CCNc1nc(NCCCCCCCCCCCC)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To 170 mg (0.44 mmol) of 2-chloro-4-dodecylamino-6-nitroquinazoline was added 1.70 ml (22.66 mmol) of allylamine, and then the resulting mixture was stirred at room temperature overnight. After water was added to the reaction solution, crystals thus precipitated were filtered to give 170 mg (93.4%) of the title compound.
Reaction SMILES: N[C:2]1C=C(C#N)C=CC=1NC1N=CC(CC(N)=O)=C(NCC2C=C(F)C=C(F)C=2)C=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][C:33]=1[NH:40][C:41]1[N:46]=[CH:45][C:44]([CH2:47][C:48]([NH2:50])=[O:49])=[C:43]([NH:51][CH2:52][C:53]2[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=2)[CH:42]=1>>[C:38]([C:35]1[CH:36]=[CH:37][C:32]2[N:31]=[CH:2][N:40]([C:41]3[N:46]=[CH:45][C:44]([CH2:47][C:48]([NH2:50])=[O:49])=[C:43]([NH:51][CH2:52][C:53]4[CH:54]=[C:55]([F:60])[CH:56]=[C:57]([F:59])[CH:58]=4)[CH:42]=3)[C:33]=2[CH:34]=1)#[N:39]
Reactant: N#Cc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c(N)c1
Reactant: N#Cc1ccc(N)c(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c1
Product: N#Cc1ccc2ncn(-c3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)c2c1

Procedure:
From the mixture of 6-[(2-amino-4-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide and 6-[(2-amino-5-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide in a manner similar to step 2 of Example 365, the title compound was obtained as a yellow solid (yield 45%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C[CH2:33][N:34](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:34][CH3:33])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol) in dry CH2Cl2:DMF (2.0:0.1 mL), added DIEA (29 μL, 0.16 mmol) and PyBOP® (46 mg, 0.088 mmol). After stirring the mixture at RT for 15 minutes, methanamine was bubbled through the solution for 15 minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by methanamine bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 20-45_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-methylacetamide. (46 mg, 0.11 mmol, 68%).
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:21]([OH:23])=[O:22])[C:19]=2[CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl(O)(=O)(=O)=O.[H][H]>[Pd].C(O)(=O)C>[CH2:1]([CH:12]1[CH2:20][C:19]2[C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cc2c(C(=O)O)cccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCCC1Cc2c(cccc2C(=O)O)N1
Yield: 73.6 %

Procedure:
A mixture containing 2-(n-undecyl)indole-4-carboxylic acid (25.8 g), palladium on charcoal (5% w/w, 5.2 g), 72% w/v aqueous perchloric acid (26 ml) and glacial acetic acid (200 ml) was heated by external application of steam while being shaken under an atmosphere of hydrogen. When the required hydrogen had been taken up, the hot mixture was filtered through diatomaceous earth, the residue was washed with fresh hot glacial acetic acid (200 ml), and the combined filtrates were concentrated in vacuo to about 75 ml. The residue was poured onto crushed ice and water, and 50% w/v aqueous sodium hydroxide was added to pH 12. Acetic acid was added to pH B 4-5 and the product was collected by filtration and washed with water. Recrystallisation from methanol yielded (RS)-2-(n-undecyl)indoline-4-carboxylic acid (19.1 g) in the form of a buff solid, m.p. 105°-108° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[CH2:11]([S:10][C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(O)c(S)c(=O)o1
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccccc2)c(=O)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.0 g. (0.051 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone in 38 ml. of pyridine was added 6.4 g. (0.051 mole) of benzyl chloride portionwise with stirring at room temperature. The reaction was slightly exothermic, the temperature rising from 23° to 30°C. The reaction mixture was stirred at room temperature for 30 minutes, and then heated on the steam bath for one hour at 90°-95°C. The reaction mixture was then cooled to room temperature and poured into a mixture of ice and 80 ml. of concentrated hydrochloric acid. The gummy precipitate, thus formed, was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 7.7 g. (61%) of brown oil, which was crystallized from toluene, containing a little methylcyclohexane, to give 5.0 g. of yellow-brown crystals, m.p. 117°-126°C. Recrystallization of this substance from toluene gave the pure 3-benzylthio-4hydroxy-6-methyl-2-pyrone as cream colored crystals, m.p. 127.5°-128.5°C.
Reaction SMILES: C([O:8][C:9](=[O:16])[C@@H:10]([CH2:12][C:13]([OH:15])=[O:14])[OH:11])C1C=CC=CC=1.Cl.[C:18]([O:24]N)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>>[C:18]([O:24][O:8][C:9](=[O:16])[C@@H:10]([CH2:12][C:13]([OH:15])=[O:14])[OH:11])(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)C[C@@H](O)C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(=O)ON
Agent: Cl
Product: CC(C)(C)C(=O)OOC(=O)[C@H](O)CC(=O)O
Yield: 89 %

Procedure:
D-Malic acid monobenzyl ester prepared as described by Example 1A was allowed to react with pivalyloxyamine hydrochloride according to the method described in the preceding examples (Part B) to provide in 89% yield O-pivalyloxy-D-malic acid hydroxyamate monobenzyl ester melting at about 75° to about 76° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1
Reactant: BrCCCCOc1ccc2ccccc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCOc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 2-(4-bromobutoxy)naphthlene (1.12 g). The mixture was stirred and heated under argon at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was crystallized from dichloromethane-diethyl ether to provide 1.1 g of 4-[[4-(2-naphthalenyloxy)butyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 93°-95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C:33](=O)[CH2:34][C:35](=[O:42])[CH2:36][C:37]([O:39]CC)=[O:38])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(O)(=O)CC(C)=O.C(OCC)(=O)CC(C)=O>>[C:21]1([NH:20][C:19]([C:11]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]([CH2:31][CH2:32][C@@H:33]3[CH2:34][C@@H:35]([OH:42])[CH2:36][C:37](=[O:39])[O:38]3)[C:10]=2[CH:28]([CH3:30])[CH3:29])=[O:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CC(=O)CC(=O)CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C
Agent: CC(=O)CC(=O)O
Solvent: CCOC(=O)CC(C)=O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1

Procedure:
In a process analogous to Step 5 METHOD A, by substituting the appropriate ester or amide of acetoacetic acid for ethyl acetoacetate, one obtains the following compounds:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][C:21]2[CH:30]=[C:29]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=[CH:28]3)[C:22]=2C(O)=O)=[CH:18][C:17]=1[C@H:36]1[C@@H:41]([O:42]C(=O)C)[C@@H:40]([O:46]C(=O)C)[C@@H:39]([O:50]C(=O)C)[C@@H:38]([CH2:54][O:55]C(=O)C)[O:37]1)[CH3:14]>>[CH:22]1[C:23]2[C:29]([CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:30][C:21]=1[CH2:20][C:19]1[CH:34]=[CH:35][C:16]([O:15][CH2:13][CH3:14])=[C:17]([C@@H:36]2[O:37][C@H:38]([CH2:54][OH:55])[C@@H:39]([OH:50])[C@H:40]([OH:46])[C@H:41]2[OH:42])[CH:18]=1
Reactant: CCOc1ccc(Cc2cc3cccccc-3c2C(=O)O)cc1[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOc1ccc(Cc2cc3cccccc-3c2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 84.6 %

Procedure:
p-Toluenesulfonic acid monohydrate (40 mg) was added to a suspension of 2-(4-ethoxy-3-[(2S,3R,4R,5S,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylic acid (0.36 g) inbenzene (10 ml) and the mixture was refluxed with heating for 15 minutes. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-ethoxyphenyl]-D-glucitol (203 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:36]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C>[CH3:1][C:2]1([CH3:35])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [BH3-]C#N
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Nc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(c1ccccc1)c1ccccc1CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
53 mg of the compound of example 1 were dissolved in 1.1 ml of acetonitrile. 10.4 mg of sodium cyanoborohydride were added to this solution. Subsequently, 0.18 ml of a 37% formalin solution and 0.05 ml of glacial acetic acid were added dropwise. The mixture was stirred at room temperature for 2 h; thereafter and another 2 h later, the same amounts of sodium cyanoborohydride and formalin solution were once again added dropwise. For workup, the mixture was filtered through a silica gel cartridge and the filtrate was concentrated under reduced pressure and purified by chromatography (method [RP1]). 4-{4,4-Dimethyl-3-[2-(methylphenylamino)benzyl]-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile 59 was obtained in a yield of 60%. Molecular weight 492.17 (C27H23F3N4O2); retention time Rt=2.33 min. [B]; MS (ESI): 493.05 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][S-:13].[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][S:13][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 23 h
Yield: 90.1 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (2 g, 12.7 mmol) in dry DMF (67 mL) were added by aliquots 2 equivalents of sodium thiomethoxide (1.78 g, 25.5 mmol) followed by 3 equivalents of potassium carbonate (5.27 g, 38.2 mmol). The mixture was stirred at RT for 23 hours and then water (100 mL) was added. The mixture was extracted with EtOAc, and the combined organic layers washed successively with water (60 mL) and brine (60 mL) and then dried over MgSO4. The solvent was evaporated under vacuum to provide the title compound (2.12 g, 90%) as a yellow powder.
Reaction SMILES: [O:1]=[C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(O)C.[BH4-].[Na+]>C1COCC1>[OH:1][CH:2]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:17][CH:18]=1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8]
Reactant: CN(CC(=O)c1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CC(O)c1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
tert-Butyl 2-oxo-2-(4-morpholin-4-ylphenyl)ethyl(methyl)carbamate (1.41 g, 4.22 mmol) was stirred under N2 in dry THF (25 ml) and absolute ethanol (2 ml). Sodium borohydride (0.16 g, 4.23 mmol) was added and the reaction stirred for 18 hr then the solvents evaporated. The residue was chromatographed over silica gel (90 g) eluting with 50% ethyl acetate-hexane. The product was obtained (1.0 g, 71%) as a clear gum which slowly crystallized to give a white solid.