Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3]CC)C.[Cl:6][C:7]1[CH:26]=[CH:25][C:10]([CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][CH2:16][CH:17]3[C:22]([OH:24])=[O:23])=[CH:9][CH:8]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][CH2:16][CH:17]3[C:22]([OH:24])=[O:23])=[O:3])=[CH:25][CH:26]=1
Reactant: CCOCC
Reactant: O=C(O)C1CCCc2c(Cc3ccc(Cl)cc3)cccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1cccc2c1CCCC2C(=O)O
Reaction time: 8 h

Procedure:
To 200 ml. of ethyl ether is added 15 g. of 5-(p-chlorobenzyl)-1,2,3,4-tetrahydro-1-naphthoic acid, and a solution of 5 g. of sodium dichromate in 24 ml. of 6N sulfuric acid is added dropwise. After stirring overnight, 100 ml. of water is added and the ethereal layer is further washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the oily residue is purified by column chromatography on silica gel equilibrated with oxalic acid with chloroform as the eluent and, then, recrystallized from benzene. The described procedure gives 5-(p-chlorobenzoyl)-1,2,3,4-tetrahydro-1-naphthoic acid, melting point: 152.5°-153.5° C.
Reaction SMILES: [CH3:1]OC1C=C(O)C(Cl)=CC=1C(OC)=O.[C:15]1([CH3:22])[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(N1CCCC1CN)C>CO>[C:15]1([CH3:1])([CH3:22])[CH:20]=[CH:19][CH:18]=[C:17]2[CH2:21][CH:16]12
Reactant: Cc1ccccc1C
Reactant: COC(=O)c1cc(Cl)c(O)cc1OC
Agent: CCN1CCCC1CN
Solvent: CO
Product: CC1(C)C=CC=C2CC21

Procedure:
In a 500 ml flask with a 40 cm Vigreux column, there are put 32 g (0.15 mole) of methyl 2-methoxy-4-hydroxy-5-chlorobenzoate, 120 ml of xylene and 23 g of levo 1-ethyl-2-aminomethylpyrrolidine. It is heated gently. A solution is obtained. The methyl alcohol formed in the form of a methanol-xylene azeotrope is distilled at 60°-62° C in about an hour. At the end of the reaction, 10 ml of xylene is distilled at 135° C. In the distillate, 5 ml of alcohol are recuperated for 6 ml theoretical.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:30][CH2:31][S:32][CH2:33][C@@H:3]12.[Li+].[OH-]>O1CCOCC1>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:30][CH2:31][S:32][CH2:33][C@@H:3]12
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-ethyl 4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate (180 mg, 0.385 mmol) was taken up in dioxane (2081 μl) and LiOH (1N, 2310 μl, 2.310 mmol) was added. The reaction was stirred 16 h at room temperature. The reaction was concentrated in-vacuo and the residue was taken up in water (5 mL) and acidified (4.5N HCl) to pH 4. A tan precipitate formed which was filtered and the solids were collected, dried and determined to be the product (166 mg, 98%) as a tan solid. [M+H] calc'd for C22H25N5O3S, 440; found, 440.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[Cl:15][C:16]1[CH:17]=[C:18]2[C:27](=[C:28]([Cl:30])[CH:29]=1)[C:21]1([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[NH:20][C:19]2=[O:31]>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:27](=[C:28]([Cl:30])[CH:29]=1)[C:21]1([CH2:26][CH2:25][N:24]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:14])[F:13])[CH2:23][CH2:22]1)[NH:20][C:19]2=[O:31]
Reactant: O=C1NC2(CCNCC2)c2c(Cl)cc(Cl)cc21
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Product: O=C1NC2(CCN(C(=O)Cc3ccccc3C(F)(F)F)CC2)c2c(Cl)cc(Cl)cc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 31 using 2-(2-(trifluoromethyl)phenyl)acetic acid and 5,7-dichlorospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 3 tR=1.246, min, m/z=457; 1H NMR (CDCl3) 1.43 (d, 2H), 2.62 (m, 1H), 2.78 (m, 1H), 2.90 (t, 1H), 3.40 (t, 1H), 3.88-4.11 (m, 3H), 4.93 (d, 1H), 7.43 (m, 2H), 7.54 (m, 2H), 7.70 (d, 1H), 7.77 (s, 1H), 8.74 (s, 1H)
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([Si@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16]Br)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Mg].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>[Cu](I)I.C(OP(OCC)(OCC)=O)C.C1COCC1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([Si@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](CBr)CC2)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: I[Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](CCc3ccc(F)cc3)CC2)CC1

Procedure:
6.3 g (20 mmol) of trans-1-(trans-4-n-propylcyclohexyl)-4-bromomethyl-1-silacyclohexane was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 50 mg of triethylphosphate, 10 mg of copper iodide (I) and 3.9 g (20 mmol) of p-fluorobenzyl bromide. After a conventional after treatment, 6.1 g (yield 85%) of trans-1-(trans-4-n-propylcyclohexyl)-4-(2-(4-fluorophenyl) ethyl)-1-silacyclohexane was obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=O.[Cl:13][C:14]1[N:15]=[N:16][C:17]([NH:24][NH2:25])=[CH:18][C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:13][C:14]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:17]2[N:16]([C:4]([C:3]3[C:7]([F:12])=[CH:8][CH:9]=[C:10]([F:11])[C:2]=3[F:1])=[N:25][N:24]=2)[N:15]=1
Reactant: CC(C)(C)c1cc(NN)nnc1Cl
Reactant: O=C(Cl)c1c(F)ccc(F)c1F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1cc2nnc(-c3c(F)ccc(F)c3F)n2nc1Cl
Temperature: 160 °C
Yield: 78 %

Procedure:
2,3,6-Trifluorobenzoyl chloride (4.0 g) was added dropwise to a cooled (15° C.) solution of 3-chloro-4-(1,1-dimethylethyl)-6-hydrazinylpyridazine (4 g) in dry 1-methyl-2-pyrrolidinone (50 ml). After the addition the reaction mixture was heated at 160° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 ml), and washed twice with water (200 ml). The organic phase was separated, dried (sodium sulfate), and evaporated at reduced pressure. The residue was crystallised from dichloromethane on dilution with diethyl ether to afford the title compound (5.3 g) as a colourless solid: 1H NMR (400 MHz, DMSO-d6) δ1.52 (9H, s), 7.50 (1H, m), 7.92 (1H, m), 8.45 (1H, s); MS (ES30) m/z 341/343 [MH]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[C:9]([CH3:15])[C:8]=1[CH3:16])(=O)=O.[B:19]1(B2OC(C)(C)C(C)(C)O2)[O:23]C(C)(C)C(C)(C)[O:20]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C.O>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([B:19]([OH:23])[OH:20])=[C:8]([CH3:16])[C:9]=1[CH3:15])=[O:14]
Reactant: Cc1c(C=O)ccc(OS(=O)(=O)C(F)(F)F)c1C
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C=O)ccc(B(O)O)c1C
Temperature: 90 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
To a solution of 4-formyl-2,3-dimethylphenyl trifluoromethanesulfonate (2.5 g) in 1,4-dioxane (50 ml) was added bis(pinacolato)diboron (2.47 g), 1,1′-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloridedichloromethane complex (1:1) (1.09 g) and potassium acetate (2.61 g), and the mixture was stirred at 90° C. for 5 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated. To a suspension of the crude product in acetone (80 ml) and water (80 ml) was added ammonium acetate (1.4 g) and sodium periodate (3.95 g), and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/1) to give (4-formyl-2,3-dimethylphenyl)boronic acid (560 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](F)[CH:5]=[C:4]([CH2:9][F:10])[N:3]=1.C(O)(=[O:13])C>>[NH2:1][C:2]1[NH:7][C:6](=[O:13])[CH:5]=[C:4]([CH2:9][F:10])[N:3]=1
Reactant: CC(=O)O
Reactant: Nc1nc(F)cc(CF)n1
Product: Nc1nc(CF)cc(=O)[nH]1

Procedure:
12.1 Parts of 2-amino-4-fluoro-6-fluoromethylpyrimidine was dissolved in 200 parts of 20% aqueous acetic acid at reflux, with stirring. The mixture was heated under reflux for 1 hour then cooled. The precipitated solid was filtered, washed with 50% aqueous acetic acid and then with acetone. The solid was dried in vacuo at 140° C. to give 2-amino-6-fluoromethylpyrimidine-4-one, m.p. 237°-238° C. (decomposition).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11].Cl[O-].[Na+]>C(#N)C>[C:1]1([CH2:7][C:8]([Cl:11])=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl
Reactant: ON=CCc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Product: ON=C(Cl)Cc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Phenylacetaldehyde oxime (40.5 g, 300 mmol) was dissolved in acetonitrile (100 ml). To the solution, a 6.7% aqueous hydrochloric acid (145 g) and then an 8.5% so aqueous sodium hypochlorite (262 g, 299 mmol) were added dropwise at -10° C. over 2.3 hours. The mixture was stirred at -5° C. for 30 minutes and then combined with toluene (200 ml) for extraction. The separated organic layer was washed twice with water (200 ml). Reversed phase HPLC revealed that the extract contained 40.3 g (238 mmol, yield 79%) of the desired compound. The solution was used in the next step without concentration.
Reaction SMILES: [OH-:1].[Na+].C([C:5]1[C:6]2[CH:23]=[CH:22][CH:21]=[N:20][C:7]=2[N:8]([CH:17]2[CH2:19][CH2:18]2)[C:9]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:10]=2[N:11]=1)#N.[CH3:24]O>>[CH:17]1([N:8]2[C:7]3[N:20]=[CH:21][CH:22]=[CH:23][C:6]=3[C:5]([O:1][CH3:24])=[N:11][C:10]3[C:12]([CH3:16])=[CH:13][CH:14]=[N:15][C:9]2=3)[CH2:19][CH2:18]1
Reactant: Cc1ccnc2c1N=C(C#N)c1cccnc1N2C1CC1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: COC1=Nc2c(C)ccnc2N(C2CC2)c2ncccc21
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of 2N sodium hydroxide (6 mL, 1.2 mmol) was added in three portions over two hr to a solution of 6-cyano-11-cyclopropyl-4-methyl-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.30 g, 1.1 mmol) in methanol (50 mL) at room temperature. The mixture was stirred overnight, and then concentrated in vacuo. The residue was dissolved in ethyl acetate (150 mL) and washed succesively with water and brine. After drying (MgSO4), the solution was concentrated and crystallized from acetonitrile to give 0.20 g (65%) of the title compound. A second recrystallization from methanol provided pure product, m.p. 191°-192° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]O)[C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:40][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][N:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=1)[C:25](=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(c1ccccc1)N(CCCCCO)CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(c1ccccc1)N(CCCCCBr)CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Part C. A solution of the alcohol prepared in Part B above (4.71 g, 8.93 mmol) and carbon tetrabromide (4.15 g, 12.5 mmol) in methylene chloride (30 mL) was cooled to 0° C., and treated with a solution of triphenylphosphine (3.28 g, 12.5 mmol) in methylene chloride (30 mL) dropwise. After stirring overnight, the solution was evaporated, and the residue was separated by flash chromatography (1:1 ethyl acetatehexane) to afford the product, N-(5-bromopentyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-benzamide, as a low-melting solid (3.71 g, 6.28 mmol, 70%). 1H NMR (CDCl3): 11.08 (1H, br s); 7.61-7.20 (15H, m); 3.66-3.00 (8H, m); 1.98-1.40 (12H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C)[C:3]=1[S:9]([Cl:12])(=[O:11])=[O:10].[F:13][C:14]([F:26])([F:25])C1C=CC=CC=1S(Cl)(=O)=O.N1C=CC=CC=1.C(Cl)Cl>O>[F:13][C:14]([F:26])([F:25])[C:5]1[CH:4]=[C:3]([S:9]([Cl:12])(=[O:10])=[O:11])[CH:2]=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-6-methylbenzenesulfonyl chloride (8, 7.82 g, 34.8 mmol) was added to a solution of 7 (8.83 g, 31.6 mmol) in pyridine (7.67 ml, 95.0 mmol) and the reaction mixture was stirred at room temperature overnight. CH2Cl2 and H2O were added to the reaction mixture and the organic phase was separated, washed with water and sat. NaCl solution, dried over Na2SO4 and concentrated to obtain the product 9, which was employed directly as such in the next stage.
Reaction SMILES: OC1C=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[N:13]2)=[N:6]C=1.N1C=C[CH:33]=[CH:32][CH:31]=1.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>ClCCl.C1(C)C=CC=CC=1>[CH:32]([C:37]([O:39][C:40]1[CH:42]=[N:6][C:5]([C:8]2[CH:29]=[CH:28][CH:27]=[C:10]([CH2:11][N:12]3[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]4[CH:26]=[CH:25][CH:24]=[C:21]([C:22]#[N:23])[CH:20]=4)=[N:13]3)[CH:9]=2)=[N:4][CH:41]=1)=[O:38])([CH3:33])[CH3:31]
Reactant: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)c1
Reactant: CC(C)OC(=O)Cl
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)C(=O)Oc1cnc(-c2cccc(Cn3nc(-c4cccc(C#N)c4)ccc3=O)c2)nc1

Procedure:
1.14 g (3 mmol) of 3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile are suspended in 15 ml of dichloromethane, 242 μl [3 mmol) of pyridine are added, and 3.0 ml of 1 M isopropyl chloroformate solution in toluene are added dropwise at 0-5° C. with stirring. The mixture is stirred at room temperature for 24 h. The reaction mixture is filtered, the mother liquor is washed with water, dried, filtered and stripped off to dryness. The residue is purified by column chromatography on silica gel. The product is triturated with ether, filtered off with suction and dried.
Reaction SMILES: [Li]CCCC.CN(C)CCN(C)C.[CH2:14]([C:17]1[C:30]2[CH2:29][C:28]3[C:23](=[C:24]([CH2:40][CH2:41][CH3:42])[C:25]([CH2:37][CH2:38][CH3:39])=[C:26]([CH2:34][CH2:35][CH3:36])[C:27]=3[CH2:31][CH2:32][CH3:33])[CH2:22][C:21]=2[C:20]([CH2:43][CH2:44][CH3:45])=[C:19]([CH2:46][CH2:47][CH3:48])[C:18]=1[CH2:49][CH2:50][CH3:51])[CH2:15][CH3:16].CI>CCCCCC>[CH2:43]([C:20]1[C:21]2[C:30](=[CH:29][C:28]3[C:23]([CH:22]=2)=[C:24]([CH2:40][CH2:41][CH3:42])[C:25]([CH2:37][CH2:38][CH3:39])=[C:26]([CH2:34][CH2:35][CH3:36])[C:27]=3[CH2:31][CH2:32][CH3:33])[C:17]([CH2:14][CH2:15][CH3:16])=[C:18]([CH2:49][CH2:50][CH3:51])[C:19]=1[CH2:46][CH2:47][CH3:48])[CH2:44][CH3:45]
Reactant: CCCc1c(CCC)c(CCC)c2c(c1CCC)Cc1c(CCC)c(CCC)c(CCC)c(CCC)c1C2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Product: CCCc1c(CCC)c(CCC)c2cc3c(CCC)c(CCC)c(CCC)c(CCC)c3cc2c1CCC
Temperature: 50 °C
Yield: 98 %

Procedure:
After 2.2 equivalents of n-BuLi and 2.2 equivalents of tetramethylethylenediamine were added to the hexane solution of 9,10-dihydro-1,2,3,4,5,6,7,8-octapropylanthracene at room temperature, the mixture was heated at 50° C. for 3 hours. The reaction solution was cooled to room temperature and 1.1 equivalent of methyl iodide was added thereto. Stirring for an hour produced the title compound in the NMR yield of 98%. The compound was treated with 3N hydrochloric acid, and washed with saturated sodium hydrogencarbonate aqueous solution and brine. The organic phase was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the pure title compound in the yield of 96%. In this case, purification by column chromatography, etc. was unnecessary.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C1(CN)CCCCC1.[O:20]=[C:21]1[C:29]2([CH2:33][O:32][C:31]3[CH:34]=[C:35]4[C:39](=[CH:40][C:30]2=3)[CH2:38][CH2:37][O:36]4)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH2:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:20]=[C:21]1[C:29]2([CH2:33][O:32][C:31]3[CH:34]=[C:35]4[C:39](=[CH:40][C:30]2=3)[CH2:38][CH2:37][O:36]4)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])=[O:47])=[CH:49][CH:50]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: Nc1ccccc1C(F)(F)F
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1ccccc1C(F)(F)F)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-(trifluoromethyl)aniline to replace cyclohexanemethylamine, and 4[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-[2-(trifluoromethyl)phenyl]benzamide was obtained (53%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.39 (d, J=8.2 Hz, 1H), 8.17 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.62 (dd, J=15.9, 7.9 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.31-7.14 (m, 4H), 7.04 (dd, J=7.6, 7.6, 0.7 Hz, 1H), 6.76 (d, J=7.7 Hz, 1H), 6.47 (s, 1H), 6.43 (s, 1H), 5.02 (ABq, 2H), 4.85 (ABq, 2H), 4.54 (t, J=8.7 Hz, 2H), 3.10-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.0, 164.9, 161.9, 161.3, 142.6, 141.7, 140.4, 133.8, 133.1, 132.7, 128.8, 128.0, 127.7, 126.2, 124.6, 124.1 (2C), 123.7, 120.0, 118.8, 109.0, 93.3, 80.6, 72.4, 57.7, 43.8, 29.0; MS (ES+) m/z 557.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22](S(O)(=O)=O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[N:37]([CH:39]=[O:40])C>>[CH2:29]([O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][CH2:2][C:7]2[N:37]=[C:39]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:40][C:6]=2[CH3:5])=[CH:10][C:11]=1[CH2:16][CH2:17][CH3:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCc1cc(OCc2ccccc2)ccc1O
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OCc1ccccc1
Temperature: 55 °C

Procedure:
A mixture of 4-benzyloxy-2-propylphenol (3.89 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-ly) ethyl ester (4.67 mmol) (see Ex. 1, part F) and cesium carbonate (1.65 g 5.06 mmol) in anhydrous DMF (8 mL) was heated for 18 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (100 mL) and water (50 mL), washed with brine (50 mL), dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using the Biotage FlashElute chromatography system using a 40 L normal phase cartridge, eluting with 10-15% ethyl acetate/hexanes to give 4-[2-(4-benzyloxy-3-propylphenoxy)ethyl]-5-methyl-2-phenyloxazole.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:33]([F:36])([F:35])[F:34])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]2([NH:26]S(C(C)(C)C)=O)[CH2:25][O:24][CH2:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl.CCOCC>C1CCCCC1>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([C:33]([F:36])([F:34])[F:35])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]2([NH2:26])[CH2:23][O:24][CH2:25]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)NC1(c2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)COC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C4(N)COC4)ccc3c2C(F)(F)F)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {3-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-oxetan-3-yl}-amide (332 mg, 0.632 mmol) in methylene chloride (7 mL, 100 mmol) was added 2.0 M of hydrogen chloride in ether (0.632 mL, 1.26 mmol) and stirred for 10 min. A precipitate formed and cyclohexane was added to dilute the mixture. After removal of solvent, the residue was dissolved in methylene chloride, 1M aq. NH4OH was added, the extracted organic layer was dried and subjected to silica gel chromatography with MeOH/CH2Cl2 (20-40%) to give 3-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl) oxetan-3-amine as a solid (213.7 mg, 80%). LCMS: Rf=1.67 min 405.20 ([M−16]). 1H NMR (400 MHz, CHLOROFORM-d) δ=8.27 (d, J=9.3 Hz, 1H), 7.93 (d, J=9.2 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.81 (dd, J=2.1, 9.3 Hz, 1H), 7.33 (d, J=9.2 Hz, 1H), 5.06 (d, J=6.5 Hz, 2H), 4.82 (d, J=6.5 Hz, 2H), 4.38-4.24 (m, 1H), 2.20 (d, J=12.4 Hz, 2H), 1.93-1.82 (m, 2H), 1.55 (br. s., 2H), 1.41-1.09 (m, 5H), 0.89 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH2:25]1[CH2:39][O:38][C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH2:28][CH2:29][CH2:30]Br)[O:26]1.O>COCCOC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:30][CH2:29][CH2:28][C:27]1([O:26][CH2:25][CH2:39][O:38]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Reactant: BrCCCC1(c2ccccc2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(CCCC1(c2ccccc2)OCCO1)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of 1.1 g of 2-(1-naphthylmethyl)malonic acid diethyl ester in 20 ml of dry 1,2-dimethoxyethane was added 0.22 g of a 50% sodium hydride (suspension in oil) under cooling, the mixture was stirred for 1 hour. To the reaction mixture was added 1.0 g of 4,4-ethylenedioxy-4-phenylbutyl bromide obtained, the mixture was heated under reflux for 17 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 1.2 g of 2-(4,4-ethylenedioxy-4-phenylbutyl)-2-(1-naphthylmethyl)malonic acid diethyl ester.