Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(NCc2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(NCc2ccccc2)n1

Procedure:
The reaction described in Preparation 15 was repeated, but using 5 g of ethyl 2-benzylaminothiazole-4-carboxylate, 1.4 g of lithium aluminum hydride and 100 ml of tetrahydrofuran, giving the title compound as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=1[O:40][CH3:41].CN(C)CCN(C)C.C([Li])CCC.[CH3:55][S:56]C>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:41][O:40][C:25]1[C:26]([O:36][CH2:37][O:38][CH3:39])=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:30][CH2:31][O:32][CH3:33])[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[C:7]([S:56][CH3:55])=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: CSC
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(SC)c(OCOC)c2OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.51 Grams of 2,2'-pentamethylenebis[1,4-dimethoxy- 3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 40 ml of tetrahydrofuran with 4 ml of hexamethylphosphoric triamide, to this solution was added 0.55 ml of N,N,N',N'-tetramethylethylenediamine and the whole mixture was cooled to -78° C., on a dry ice-acetone bath. Then, 2.41 ml of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 30 minutes. Next, 0.25 ml of dimethyl sulfide was added to the reaction mixture and stirred overnight. The solvent was removed by evaporation under reduced pressure, then the residue obtained was extracted twice with 100 ml of ethyl acetate, then the ethyl acetate layer was washed twice with 100 ml of water, and twice with a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue obtained was purified by means of a preparative thin layer chromatography (thickness: 2 mm, adsorbent: Merck Art 5717 silica gel, developing solvent: 20% ethyl acetate-n-hexane). There were obtained 572 mg of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(methylthio)phenyl]pentane, as well as 522 mg of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)-5-(methylthio)benzene].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1)[C:14]([O:16]C)=[O:15].[OH:35][Li].O>C1COCC1.O>[C:14]([CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][Si:25]([CH:29]([CH3:30])[CH3:31])([CH:32]([CH3:33])[CH3:34])[CH:26]([CH3:27])[CH3:28])=[CH:20][CH:19]=1)[CH2:12][NH:3][C:2]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:4]([OH:35])=[O:11])=[O:1])([OH:16])=[O:15]
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(C(CNC(=O)c2ccccc2C(=O)O)C(=O)O)cc1)(C(C)C)C(C)C
Reaction time: 1.5 h

Procedure:
To methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(triisopropylsilyloxy)phenyl)propanoate (E3) in THF/H2O was added LiOH.H2O, and the solution was stirred for 1.5 h or until conversion to product was visible by LC-MS. The solution was then poured into EtOAc/NH4Cl(sat)/1 N HCl (3:1), and the aqueous layer was further extracted with EtOAc. The organics were dried (Na2SO4), filtered, evaporated, and dried to give crude 2-(2-carboxy-2-(4-(triisopropylsilyloxy)phenyl)ethylcarbamoyl)benzoic acid (E4).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([N:12]2[C:15](=[O:16])[C@@H:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[C@H:13]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[C:1]1([C@H:7]([NH:9][C:10]([N:12]2[C:15](=[O:16])[C@@H:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[C@H:13]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:11])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@H]1[C@H](Sc2cccc([N+](=O)[O-])c2)C(=O)N1C(=O)N[C@H](C)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1[C@H](Sc2cccc(N)c2)C(=O)N1C(=O)N[C@H](C)c1ccccc1
Temperature: 50 °C
Yield: 63.6 %

Procedure:
To a solution of 85b (17 mg, 38 umol) in ethyl acetate (1 mL) at room temperature was added tin chloride monohydrate (2.5 eq.) and the solution was heated to 50° C. After 1 h the solution was concentrated in vacuo. The residue was purified by column chromatography using a gradient of hexane/ethyl acetate 20-100% as eluent to yield 87 (10 mg, 63%). Product MS: 414.1 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:43](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>O.C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH2:43])=[O:28])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(N)=O)cc3C(F)(F)F)ncc21
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
A mixture of 0.1013 g (0.208 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204), 5 mL of dimethylformamide, 0.107 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 0.25 mL (1.435 mmole) of diisopropylethylamine was stirred for 20 minutes, then 0.0444 g (0.830 mmole) of ammonium chloride was added. The reaction mixture was stirred for 1.5 hours and then 150 mL of ethyl acetate and 25 mL of water was added. The organic layer was washed with 25 mL of ammonium chloride solution, 25 mL of water, 25 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.048 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzamide (I-213).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.7 %

Procedure:
38.1 A solution of 530 mg (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.2) in 5 ml pyridine was cooled to 0° C. under an argon atmosphere and treated with 664 mg 4-toluenesulfonyl chloride. The mixture was slowly warmed to room temperature and stirred for 6 hrs. The pyridine was distilled off. The residue was taken up in CH2Cl2 and 10% aq. Na2CO3. The organic phase was washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient: cyclohexane->cyclohexane/EtOAc 7:3) to give 628 mg (3S,4S)-3-azido-4-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as viscous yellow oil. MS 405.3 ([M+Na]+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[C:17]([F:20])([F:19])[F:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[C:17]([F:19])([F:18])[F:20])=[O:9])=[CH:6][N:5]=[C:4]([NH:42][CH:39]2[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)ccc2C(F)(F)F)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3C(F)(F)F)c(N)n2)CC1

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(5-fluoro-2-trifluoromethyl-phenyl)-methanone (Example 199) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C18H20N5O3SF4 [(M+H)+] 462.1218, observed 462.1222.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1>C(O)(=O)CC>[C:2]([O:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1)(=[O:1])[CH2:3][CH3:15]
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Solvent: CCC(=O)O
Product: CCC(=O)OCc1cc2c3ccccc3[nH]c(=O)n2n1
Yield: 69 %

Procedure:
2-(Hydroxymethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one (3.0 g, 0.0139 mole) is suspended in 250 ml of propionic acid and the mixture refluxed overnight under nitrogen. The resultant solution is stripped to a solid and recrystallized from absolute ethanol to give 2.6 g (69% yield) of analytically pure title compound, m.p. 184°-186°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.Cl[CH2:17][S:18]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH2:17][S:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH:8]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(OCCCCCl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCCCCl)cc1CS(=O)(=O)c1cccc2ccccc12
Reaction time: 5 h
Yield: 80.4 %

Procedure:
A mixture of 1-(4-chloro-butoxy)-4-nitrobenzene (1.28 g, 5.6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (1.6 g, 6.72 mmoles) was stirred in THF (50 ml) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (16.8 ml, 16.8 mmoles) over a half an hour period. Temperature was allowed to rise to −40° C., and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (1.94 g, 4.5 mmoles).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:28])[C@H:13]2[C@H:22]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:21][CH2:20][C:15]3(OCC[O:16]3)[CH2:14]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:28])[C@@H:13]2[CH2:14][C:15](=[O:16])[CH2:20][CH2:21][C@H:22]2[N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1CC2(CC[C@H]1N1CCCC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1CC(=O)CC[C@H]1N1CCCC1
Temperature: 58 °C
Reaction time: 1 h
Yield: 235841.7 %

Procedure:
A mixture of trans-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-7-yl]benzeneacetamide (4.5 g, 0.01 mmole) prepared by procedures described above, and 100 ml of 3 N HCl solution was stirred under N2 atmosphere while 150 ml of acetone was added. The mixture was stirred at 58° C. for one hour and cooled to room temperature. Removed the acetone in vacuo and neutralized the mixture by addition of solid NaHCO3 with intermittant cooling of the mixture in a dry ice-acetone bath. Extracted the aqueous layer with CHCl3 ; the CHCl3 extracts were dried (Na2SO4) and concentrated in vacuo to a pale yellow oil (5 g). Dissolved the oil in CHCl3 and treated the solution with ethereal HCl. Separated the solvent from a pale yellow gum and dissolved the gum in CHCl3. Diluted the CHCl3 solution with ether and refrigerated overnight. Filtered the white solid which deposited and dried in vacuo at 40° C. to give a total of 4.95 g of the titled cyclohexanone. Mass spectrum m/e 382/384 (M+, chlorine isotopic peaks). IR NH (2600, 2480), C=O (ketone) 1725, C=O (amide) 1645 cm-1 and nmr spectra were consistent with the structure assignment.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([CH3:19])[NH:8][C:9](OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[CH2:21](I)[CH:22]=C.[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[C@H:7]([CH3:19])[NH:8][CH2:9][CH:21]=[CH2:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
Benzyloxycarbonyl-L-alanine t-butyl ester (10.0 g, 35.8 mmol) was dissolved in dry THF. Allyl iodide (7.4 mL, 78.8 mmol) was added followed by sodium hydride (1.80 g, 45.0 mmol). The reaction was left stirring at room temperature overnight. The reaction was evaporated and taken up in ethyl acetate. It was extracted with water and treated with sodium metabisulfite. The ethyl acetate was extracted with 1N aqueous sodium carbonate, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The crude product was flash chromatographed (silica gel, hexane followed by hexane:ethyl acetate 95:5) to give N-benzyloxycarbonyl, N-allyl-L-alanine t-butyl ester (6.8 g, 60%). 1H NMR (CDCl3) δ7.33 (s, 5H), 6.17-5.67 (m, 1H), 5.20 (d, 4H), 1.75-1.70 (s/d, 12H).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.B.O1CCCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 2-phenoxybenzoic acid (20.8 g) in tetrahydrofuran (400 ml), 14.6 ml of borane-tetrahydrofuran complex (1M tetrahydrofuran solution) was added, and the reaction solution was stirred at 50° C. for 4 hours. The reaction solution was cooled, then water was added, and the mixture was extracted with chloroform. The combined organic layers were washed with 1N aqueous sodium hydroxide and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford the title compound as a colorless oil.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]2[CH2:13][CH:12]([NH:14][NH2:15])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.CN(C)/[CH:28]=[CH:29]/[C:30]([C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[OH:39])=O>C(O)C>[C:16]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:13][CH:12]([N:14]3[C:30]([C:32]4[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=4[OH:39])=[CH:29][CH:28]=[N:15]3)[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)/C=C/C(=O)c1cc(F)ccc1O
Reactant: NNC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc(F)cc1-c1ccnn1C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(diphenylmethyl)-3-hydrazinoazetidine dihydrochloride (Preparation 690, 1.25 g, 4.30 mmol) was stirred in ethanol (20 ml) and acetic acid (8 ml) for 30 minutes with ice cooling to give a suspension. To this cold suspension was added (2E)-3-(dimethylamino)-1-(5-fluoro-2-hydroxyphenyl)prop-2-en-1-one (Preparation 221, 900 mg, 4.3 mmol), stirred at 0° C. for 1 hour then allowed to warm up to room temperature over 18 hours. The reaction mixture was evaporated and then partitioned between ethyl acetate (100 ml), water (50 ml) and saturated aqueous sodium hydrogencarbonate solution (30 ml). The organic layer was separated and back-washed with saturated aqueous sodium chloride solution (2×20 ml), dried over sodium sulphate, filtered and evaporated. The solid was triturated with diethyl ether and the off-white solid filtered. The solid was crystallized from ethyl acetate:hexane (1:4) to give the title compound as colourless crystals were. Yield 490 mg 29%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:34]=[C:33]([CH3:35])[C:28]3[NH:29][C:30](=[O:32])[O:31][C:27]=3[CH:26]=2)[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][C:33]1[C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=[C:25]([O:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=2)[CH:34]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
40 mg (0.18 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 50 mg (0.18 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.10 mL (0.58 mmol) DIPEA were combined in 1.8 mL DMF and stirred for 1 h at RT. Then another 40 mg (0.18 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo-[4,5-b]pyridin-2-one were added and the mixture was stirred overnight. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down, the precipitate was suction filtered and dried i. vac.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[C:13]3[C:14]([CH3:34])=[C:15]([N:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[CH2:22][CH2:21]4)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:36])[CH3:35])=[CH:5][CH:4]=1>C(O)C>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:34])=[C:15]([N:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[CH2:22][CH2:21]4)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:35])[CH3:36])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C(F)(F)F)cc3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(C(F)(F)F)cc3)C(C)(C)O4)CC2)cc1
Yield: 93 %

Procedure:
Using 3-(4-(trifluoromethyl)phenyl)-5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 69, the title compound was synthesized in the same manner as in Example 46. Yield 93%. mp. 208–211° C. (ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]Br)=[C:6]([F:8])[CH:7]=1.[CH2:12]1[NH:19][CH2:18][CH2:17][S:14](=[O:16])(=[O:15])[CH2:13]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][N:19]2[CH2:18][CH2:17][S:14](=[O:16])(=[O:15])[CH2:13][CH2:12]2)=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(Br)cc(F)c1CBr
Reactant: O=S1(=O)CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN(Cc2c(F)cc(Br)cc2F)CC1

Procedure:
A solution of 3.8 g (11.3 mmol) 5-bromo-2-bromomethyl-1,3-difluoro-benzene, 1.83 g (13.6 mmol) thiomorpholine dioxide and 1.88 ml (13.6 mmol) triethylamine in 40 ml dichloromethane is stirred at room temperature for 20 h. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is taken up in diethylether, vigorously stirred, and the title compound is obtained after filtration as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].[Br:22]Br>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[C:14]([Br:22])[C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc(N)c(NC)c1C#N
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C(C)=O)c1cc(Br)c(N)c(NC)c1C#N
Yield: 52.7 %

Procedure:
To a solution of 2-(4-amino-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethyl ester from Example 4 (9.02 g, 31.2 mmol) in CHCl3 (90 mL) was added bromine (4.98 g, 31.2 mmol) dropwise at ambient temperature. After the addition of bromine, the reaction mixture was diluted with ethyl acetate (800 mL). This solution was washed successively with sat. NaHCO3 solution and brine and dried. The residue after evaporation was purified by flash chromatography in hexanes/EtOAc 2:1 to yield 2-(4-amino-5-bromo-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethyl ester as an oil (6.06 g, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22](OB(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=3)=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(Br)ccc2cc1OC
Reactant: COc1cccc(OB(O)O)c1
Product: COC(=O)c1cc2cc(-c3cccc(OC)c3)ccc2cc1OC
Yield: 66 %

Procedure:
The compound is prepared by the reaction of 7-bromo-3-methoxy-2-naphthoic acid methyl ester (2.2 g, 7.45 mmol, 1 eq) with 3-methoxyphenylboric acid (1.37 g, 8.95 mmol, 1.5 eq) according to method A. Purification by column chromatography with a gradient of hexane/dichloromethane 1/1 to 3/7 and dichloromethane/methanol 95/5 as the eluent yielded the desired compound in a yield of 66%, 1.58 g.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([CH2:10]I)=[O:9])=[CH:4][CH:3]=1.[Na].[K].[OH:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1>>[OH:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[CH:22][C:23]([O:25][CH2:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:12]=[CH:13][C:2]([OH:1])=[CH:3][CH:4]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(C=Cc1ccc(O)cc1)CI
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: [K]
Agent: [Na]
Product: O=C(C=Cc1ccc(O)cc1)COC(=O)C=Cc1ccc(O)cc1

Procedure:
Bis-demethoxycalebin-A (4-Hydroxycinnamoylmethyl 4-hydroxycinnamate, 10d) was prepared by reacting 4-hydroxycinnamoyliodomethane with sodium or potassium salt of 4-hydroxycinnamic acid with reaction steps and conditions maintained as mentioned in the general synthetic scheme discussed herein above in Para 0010. The yield of the product was 55%.