Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:34][CH:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added 1-methylpiperidin-4-amine (35 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 60 as a solid (22 mg).
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH:18]1(O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CCOCC.CN(C)C=O>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCCCC1
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: O=C(O)C(C(=O)OC1CCCCC1)c1ccccc1

Procedure:
Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 mL) was treated with thionyl chloride (8.92 g, 5.4 mL, 0.07 mol) and one drop of N,N-dimethylformamide. The mixture was heated at 40°-50° C. for 3 hours. The clear solution was distilled under vacuum. The oily residue was redissolved in dry ether (40 mL), the solution was treated with cyclohexyl alcohol (0.075 mol, 7.9 mL) and refluxed for 2 hours. The mixture was worked up as before to give an oily product which crystallized on standing. Recrystallization was carried out from a benzenepetroleum ether (40°-60°) mixture to give a white crystalline product.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([OH:12])[CH2:9][CH2:10][CH3:11].S([O-])([O-])(=O)=O.[Mg+2]>[Bi](Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:6]([O:7][C:1]1([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:1][CH2:2][CH3:3]
Reactant: O=C1CCCCC1
Reactant: CCCCO
Agent: Cl[Bi](Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CCCCOC1(OCCCC)CCCCC1
Temperature: 10 °C
Reaction time: 10 h
Yield: 182.2 %

Procedure:
In a 300-ml three-necked flask, 98 g of cyclohexanone, 148 g of n-butanol, 50 g of anhydrous magnesium sulfate, 2 mg of bismuth chloride and 80 g of toluene were charged. The resulting mixture was stirred at 10° C. under atmospheric pressure for 10 hours in a nitrogen atmosphere. After magnesium sulfate was removed from the reaction mixture, the solvent (toluene) and unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 207.7 g of cyclohexanone dibutyl acetal (yield: 89.4%).
Reaction SMILES: [F:1]C1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:19](=O)[C:18]3[C:17](O[Si](CC)(CC)CC)=[C:16]4[C:11](C=CC=N4)=[C:10](O)[C:9]=3[C:8]2=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CCO[CH2:42][CH3:43].[CH2:44]([CH2:47]OC)OC>>[F-:1].[CH2:44]([N+:7]([CH2:6][CH2:5][CH2:31][CH3:32])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:19][CH2:18][CH2:17][CH3:16])[CH2:47][CH2:42][CH3:43]
Reactant: CCOCC
Reactant: COCCOC
Reactant: CC[Si](CC)(CC)Oc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCC[N+](CCCC)(CCCC)CCCC
Product: [F-]

Procedure:
For example, 7-(4-fluoro-benzyl)-5-hydroxy-9-triethylsilanyloxy-pyrrolo[3,4-g]quinoline-6,8-dione A6.6, (Example 12, Scheme 11) is reacted at ambient temperature in dimethoxyethane solution with one molar equivalent of a dialkyl 4-bromo-2-butenylphosphonate A6.7 (J. Med. Chem., 1992, 35, 1371) and potassium carbonate, to yield the ether product A6.8, which upon deprotection with tetrabutylammonium fluoride gives the phenol A6.9.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[N+:16]([C:19]1[CH:24]=[C:23]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1Cl)([O-:18])=[O:17].Cl>C1COCC1>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:3]=[C:2]([O:1][C:20]2[CH:21]=[CH:22][C:23]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[CH:7]=[C:6]([O:8][C:20]2[CH:21]=[CH:22][C:23]([S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 3,5-dihydroxyphenylacetate (50 mg, 0.274 mmol) in THF at rt was added NaH (24 mg, 60% dispersion in mineral oil), followed by 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (159 mg, 2 equiv.). The mixture was stirred at rt for 5 hr. The reaction was acidified with 2N HCl, extracted into EtOAc, washed with water, brine, dried and concentrated. The residue was column chromatographed (EtOAc: Hex) to give [3,5-bis-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-phenyl]-acetic acid methyl ester. 1HNMR (360 MHz, DMSO-d6) δ 8.77 (d, J=2.3 Hz, 2H), 8.33 (dd, J=2.3 & 8.9 Hz, 2H), 7.46 (d, J=8.9 Hz, 2H), 7.40 (t, J=2.4 Hz, 1H), 7.30 (d, J=2.4 Hz, 2H), 3.89 (s, 2H, CH2), 3.63 (s, 3H, OCH3). MS-EI m/z 688 [M+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC=CC=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>CO.[Pd]>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)[C:3]([O:2][CH3:1])=[O:24]
Reactant: COC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)C(=O)OC
Yield: 86.8 %

Procedure:
A solution of 2-(4-benzyloxy-benzylidene)-malonic acid dimethyl ester (14,5 g, 44.5 mmol) in methanol (300 mL) was hydrogenated at 3 atm. in the presence of 5% palladium on charcoal (1.1 g). The solution was filtered, and the filtrate evaporated under a vacuum to give 9.2 g (77%) of 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester: 1H NMR (300 MHz, CDCl3): δ 3.15 (d, 2H), 3.65 (t, 1H), 3.70 (s, 6H), 6.70 (d, 2H), 7.05 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[CH:7][CH:6]=1)[CH3:2].CC(C[AlH]CC(C)C)C.CO.O>C1(C)C=CC=CC=1>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:6]=1)[CH3:20]
Reactant: CCOC(=O)/C=C/c1ccc(C(OCC)OCC)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1ccc(/C=C/CO)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of (E)-ethyl 3-(4-(diethoxymethyl)phenyl)acrylate (1.400 g) in toluene (10 mL) was added DIBAH (1 M solution in toluene) (10 mL) at −20° C. under an Ar atmosphere. The mixture was stirred at −20° C. for 1 hour. To the mixture was added MeOH, and then the mixture was heated to room temperature. To the mixture was added water, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1) to afford (E)-3-[4-(diethoxymethyl)phenyl]prop-2-en-1-ol (1.120 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[O:13])=[N:4][CH:3]=1.[CH3:25][C:26]1[C:31]([O:32][CH3:33])=[C:30]([CH3:34])[C:29]([CH2:35][S:36]([C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[O:37])=[N:28][CH:27]=1.O.O.O.[Mg+2:52]>ClCCl.C(O)C>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:13])[C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[CH:27]=[N:28][C:29]([CH2:35][S+:36]([O-:37])[C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[C:30]([CH3:34])[C:31]=1[O:32][CH3:33].[Mg+2:52]
Reactant: COc1ccc2[n-]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 62.6 %

Procedure:
Esomeprazole magnesium trihydrate (10 g) was dissolved in a mixture of dichloromethane (50 ml) and ethanol (70 ml) at 25-30° C. Any undissolved material was filtered off. The clear solution thus obtained was spray dried with an inlet temperature of 70-80° C. and an outlet temperature of 22-42° C. The solid was further dried under vacuum at 60-65° C. for 14 to 15 hours to yield 5.82 g of esomeprazole magnesium of amorphous form.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][S:5][C:6]=1Br.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[C:11]([CH3:18])[CH:10]=1.O1[CH2:24][CH2:23]OCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[N:3]=[CH:4][S:5][C:6]=2[C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][C:23]=2[CH3:24])=[C:11]([CH3:18])[CH:10]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: C1COCCO1
Reactant: Brc1ncsc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)ccc1-c1ncsc1-c1ccc(Cl)cc1C
Temperature: 90 °C

Procedure:
A round-bottomed flask was charged with 4,5-dibromothiazole (160 mg, 0.66 mmol), 4-chloro-2-methylphenylboronic acid (269 mg, 1.58 mmol) and Pd(PPh3)4 (38.1 mg, 0.033 mmol). After degassed, dioxane (5 mL) and aqueous sodium carbonate (3 mL, 2M, 6 mmol) was added. The reaction mixture was heated to 90° C. The progress of the reaction was monitored by TLC. After the reaction was complete, 50 mL of water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography to afford 170 mg of product as clear oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:10][C:11]([C:14]3[CH:27]=[C:26]4[O:28][CH2:29][C:23]5[C:24]6[C:25]4=[C:16]([CH2:17][O:18][C:19]=6[CH:20]=[C:21]([C:30]4[NH:34][C:33]([C@@H:35]6[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]6[C:41](=[O:54])[C@H:42]([NH:49][C:50](=[O:53])[O:51][CH3:52])[C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)=[N:32][CH:31]=4)[CH:22]=5)[CH:15]=3)=[CH:12][N:13]=2)[CH2:5]1.[CH3:55][O:56][C:57]([NH:59][C@@H:60]([CH:64]([CH3:66])[CH3:65])[C:61](O)=[O:62])=[O:58].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:55][O:56][C:57]([NH:59][C@@H:60]([CH:64]([CH3:66])[CH3:65])[C:61]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:9]1[NH:10][C:11]([C:14]2[CH:15]=[C:16]3[CH2:17][O:18][C:19]4[C:24]5=[C:23]([CH:22]=[C:21]([C:30]6[NH:34][C:33]([C@@H:35]7[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]7[C:41](=[O:54])[C@H:42]([NH:49][C:50]([O:51][CH3:52])=[O:53])[C:43]7[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=7)=[N:32][CH:31]=6)[CH:20]=4)[CH2:29][O:28][C:26]([CH:27]=2)=[C:25]35)=[CH:12][N:13]=1)=[O:62])=[O:58]
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reaction time: 1 h

Procedure:
A mixture of methyl (R)-2-((2S,4S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (90 mg, >0.123 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (24 mg, 0.135 mmol), HATU (51 mg, 0.135 mmol) in 1.5 mL 10% DIPEA in DMF was stirred for 1 hour. An additional 0.135 mmol of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid and HATU were added and stirring continued for 4 hours. The crude product was purified by reverse phase HPLC to product (28 mg) as a trifluoroacetate salt.
Reaction SMILES: [CH3:1][CH:2]1[C:45](=O)[C:5]2=[CH:6][C:7]3[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=4.[BH4-].[Na+]>C1COCC1.C(O)C>[CH3:1][C:2]1[CH2:3][C:4]2[C:5]([CH:45]=1)=[CH:6][C:7]1[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]3[C:14]([C:15]=1[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C(=O)C(C)C3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
In a 500 mL round flask, 2-methyl-9,9-ditetradecyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (20 g, 31.9 mmol) was dissolved in 150 mL of THF and 150 mL of ethanol, and then stirred. Sodium borohydride (NaBH4) (1.8 g, 47.8 mmol) was added to the reactant in five lots, and then stirred for 12 hours. The resultant mixture, after removal of solvent, was dissolved in ethylacetate, and then washed with water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials. The dried reactant was dissolved in 150 mL of toluene, and then inputted to a round flask. After that, p-toluene sulfonic acid (0.08 g) was inputted thereto, and then water was completely removed under reflux with Dean-Stark. The resultant material was cooled to room temperature, and then an aqueous ammonium chloride solution (100 mL) and 200 mL of diethyl ether were injected thereto, followed by separation of the organic layer. The organic layer collected by extracting the residue with diethyl ether was dried over magnesium sulfate, followed by removal of volatile materials, and then purified by using silica gel column chromatography, to thereby obtain 15.3 g of 2-methyl-9,9-ditetradecyl-3,9-dihydrocyclopenta[b]fluorene (yield: 78.5%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5](=[O:7])[N:6]=1.[F:8][C:9]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]#[N:23])=[CH:14][CH:13]=1>>[F:8][C:9]1[CH:27]=[C:26]([CH:28]=[C:4]2[S:3][C:2](=[NH:1])[NH:6][C:5]2=[O:7])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]#[N:23])=[CH:14][CH:13]=1
Reactant: NC1=NC(=O)CS1
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2F)c2ccccc12
Product: N#Cc1ccc(Oc2ccc(C=C3SC(=N)NC3=O)cc2F)c2ccccc12

Procedure:
4-[2-Fluoro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxy]-naphthalene-1-carbonitrile was prepared using 2-amino-thiazol-4-one and 4-(2-Fluoro-4-formyl-phenoxy)-naphthalene-1-carbonitrile following General Procedure C. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (br, 1H), 9.25 (br, 1H), 8.42 (d, J=8.21 Hz, 1H), 8.15 (d, J=8.21 Hz, 1H), 8.08 (d, J=7.82 Hz, 1H), 7.91 (m, 1H), 7.81 (m, 1H), 7.7 (dd, J=12.13 and 2.34 Hz, 1H), 7.64 (s, 1H), 7.49-7.57 (2H), 6.93 (d, J=7.83 Hz, 1H). LC/MS (m/z) [M+1]+390.2 (calculated for C21H13FN3O2S 390.1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[CH:7]=O)[CH3:2].C[Si]([C:20]#[N:21])(C)C.[NH3:22]>CO>[NH2:22][CH:7]([C:6]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[C:20]#[N:21]
Reactant: N
Reactant: C[Si](C)(C)C#N
Reactant: CCOc1cc(C=O)ccc1OC(C)C
Solvent: CO
Product: CCOc1cc(C(N)C#N)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
3-Ethoxy-4-isopropoxybenzaldehyde (WO 2004072101) (24 g, 115 mmol) was dissolved in a 7N MeOH solution of ammonia (200 mL) and the whole was cooled to 0° C. Trimethylsilyl cyanide (24 mL, 180 mmol) was added and the reaction mixture was stirred overnight with gradual warming to rt. The reaction product was concentrated to provide 2-amino-2-(3-ethoxy-4-isopropoxyphenyl)acetonitrile (29 g, 100%) as a yellow oil. The oil (23 g) was dissolved in ethyl ether (460 mL), cooled to 0° C., and HCl (g) was bubbled through the solution for 5 min. The resulting precipitate was filtered and dried on the high vac to provide Intermediate 13A (19 g, 72%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:10]([O:13]C(=O)C)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Mg]Cl)[CH:25]([CH3:27])[CH3:26]>C1COCC1.CCOCC.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:10]([OH:13])[C@@H:11]([OH:12])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[Mg]Cl
Reactant: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h

Procedure:
The oil prepared in Step 1 was dissolved under nitrogen in 100 mL of dry THF and cooled to -70° C. To this solution was added 13 mL (26 mmol) of a 2.0M solution of isobutylmagnesium chloride in ether and the stirred mixture was allowed to warm to room temperature and stir for 2 hrs. After decomposition with MeOH/H2Othe mixture was diluted with ether, washed with saturated NH4Cl solution twice, then dried and the solvents stripped off under vacuum. The residue was allowed to stand overnight in 80% MeOH-H2O containing excess ammonium hydroxide. The MeOH was stripped off and the mixture was extracted with ether. These extracts were combined, washed with water, dilute KHSO4, then dried and evaporated to give 2.36 g of a yellow glass which crystallized from 50 mL of pentane on standing overnight. The yellow-white powder obtained was recrystallized from ether-hexane and furnished the title compound (0.41 g) as white, hairy needles, mp 134-136° C., Rf (ether): single spot, 0.6. By chromatography of the mother liquors and crystallization of the appropriate fractions, an additional 0.22 g of product, mp 138-139° C., was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:16][S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(O)cc(OCc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of 3-benzyloxy-5-methylphenol (400 mg, 2.0 mmol), as prepared in step a of Example 3, in methylene chloride (10 mL) at 0° C. was treated with N,N-diisopropylethylamine (0.4 mL) and benzenesulfonyl chloride (354 mg, 2.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (200 mL) and water (50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (675 mg, 95%). 1H-NMR(300 MHz, CDCl3) δ 2.24 (s, 3H), 4.91 (s, 2H), 6.40 (t, 1H), 6.43 (s, 1H), 6.68 (s, 1H), 7.36 (m, 5H), 7.52 (t, 2H), 7.64 (d, 1H), 7.83 (t, 2H).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:40])[N:12]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([S:26]([N:29]2[CH2:38][CH2:37][C:32]3([O:36][CH2:35][CH2:34][O:33]3)[CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH2:23][CH2:24]Cl)=[C:16]([CH3:39])[CH:15]=1)[CH3:13])([CH3:9])([CH3:8])[CH3:7].[Cl-].[NH4+]>C1COCC1>[C:6]([O:10][C:11](=[O:40])[N:12]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][C:22]2([S:26]([N:29]3[CH2:38][CH2:37][C:32]4([O:36][CH2:35][CH2:34][O:33]4)[CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH2:24][CH2:23]2)=[C:16]([CH3:39])[CH:15]=1)[CH3:13])([CH3:9])([CH3:8])[CH3:7].[O:33]1[C:32]2([CH2:31][CH2:30][N:29]([S:26]([C:22]3([CH2:21][C:17]4[C:18]([CH3:20])=[CH:19][C:14]([NH:12][CH3:13])=[CH:15][C:16]=4[CH3:39])[CH2:23][CH2:24]3)(=[O:27])=[O:28])[CH2:38][CH2:37]2)[O:36][CH2:35][CH2:34]1
Reactant: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1CC(CCCl)S(=O)(=O)N1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CNc1cc(C)c(CC2(S(=O)(=O)N3CCC4(CC3)OCCO4)CC2)c(C)c1
Product: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1CC1(S(=O)(=O)N2CCC3(CC2)OCCO3)CC1
Reaction time: 0.08 h

Procedure:
n-Butyllithium (1.6 M solution in hexane, 345 μl, 0.552 mmol) was added to a solution of {4-[4-chloro-2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-butyl]-3,5-dimethyl-phenyl}-methyl-carbamic acid tert-butyl ester (115.0 mg, 0.2165 mmol) in THF (3.0 ml) at −78° C. over three minutes. The mixture was stirred at the same temperature for five minutes, and then warmed and further stirred at room temperature for one hour. A 50% saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give {4-[1-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-cyclopropylmethyl]-3,5-dimethyl-phenyl}-methyl-carbamic acid tert-butyl ester and {4-[1-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-cyclopropylmethyl]-3,5-dimethyl-phenyl}-methyl-amine as a mixture (46.0 mg, 43% and 19.6 mg, 23%). This was used in the next reaction without complete purification.