Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O-][C:3]#N.[K+].[C:6]([OH:13])(=O)[CH2:7][NH:8]C(N)=O.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][C:18]2([NH:28][C:29]([NH2:31])=[O:30])[C:25]([OH:27])=[O:26]>CO>[CH3:3][C@H:7]([NH2:8])[C@H:6]([OH:13])[C:15]1[CH:16]=[CH:17][CH:22]=[CH:23][CH:24]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][C@@:18]2([NH:28][C:29]([NH2:31])=[O:30])[C:25]([OH:27])=[O:26]
Reactant: NC(=O)NC1(C(=O)O)CCOc2ccc(F)cc21
Reactant: N#C[O-]
Reactant: NC(=O)NCC(=O)O
Agent: [K+]
Agent: [Na]
Solvent: CO
Product: C[C@H](N)[C@H](O)c1ccccc1
Product: NC(=O)N[C@@]1(C(=O)O)CCOc2ccc(F)cc21

Procedure:
Later developments in the overall method of production then finally gave a process for producing sorbinil which involved the following steps, viz., (1) p-fluorophenol was first converted to β-(p-fluorophenoxy)propionitrile by treatment with acrylonitrile in the presence of Triton B; (2) the nitrile intermediate was then converted to β-(p-fluorophenoxy)propionic acid by means of hydrochloric acid; (3) β-(p-fluorophenoxy)propionic acid was then condensed in the presence of concentrated sulfuric acid at 50° C. to afford 6-fluoro-4-chromanone; (4) the latter compound was thereafter condensed with potassium cyanide and ammonium carbonate in ethanol under standard Bucherer-Berg conditions to give the racemic precursor of sorbinil, which is called dl-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione; (5) the latter racemic spiro-hydantoin was then hydrolyzed with aqueous sodium hydroxide to the corresponding spiro-amino acid, which is called 4-amino-6-fluorochroman-4-carboxylic acid; (6) the latter acid, which can not be conveniently isolated in the process, was then treated in situ with sodium or potassium cyanate (after first adjusting the pH of the aqueous solution) in order to convert the amino acid to the corresponding hydantoic acid, which is called 6-fluoro-4-ureidochroman-4-carboxylic acid; (7) the latter hydantoic acid was then resolved according to the method described by B. W. Cue, Jr. et al. U.S. Pat. No. 4,435,578 by treatment with l-(-)-ephedrine in aqueous methanol to form the l-(-)-ephedrine salt of (4S)-6-fluoro-4-ureidochroman-4-carboxylic acid; and (8) the latter crystalline salt was thereafter converted to sorbinil by heating the diastereoisomer in glacial acetic acid to effect conversion to the desired (4S)-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH2:1]([N:8]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NCc2ccccc2)cccc1NS(C)(=O)=O
Reactant: O=Cc1ccc(F)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(F)cc1

Procedure:
The product from Example 8A and 4-fluorobenzaldehyde were processed as described in Example 1C to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.07-7.32 (m, 9H), 7.00-6.85 (m, 3H), 6.10 (s, 1H), 4.03 (s, 2H), 4.02 (s, 2H), 2.95 (s, 3H), 2.33 (s, 3H); MS (ESI+) m/z 399 (M+H)+; Analysis calculated for C22H23FN2O2S 0.75 TFA: C, 58.26; H, 4.95; N, 5.79. Found: C, 58.26; H, 5.17; N, 5.63.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OCC)(=[O:18])[CH:15]([CH3:17])[OH:16]>>[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:18])[CH:15]([CH3:17])[OH:16]
Reactant: CCCCCCCCCCCCO
Reactant: CCOC(=O)C(C)O
Product: CCCCCCCCCCCCOC(=O)C(C)O
Temperature: 60 °C
Reaction time: 28 h
Yield: 80 %

Procedure:
A mixture of Novozym® 435 (1 kg), 1-dodecanol (2000 mL), and ethyl lactate (2000 mL) in a 50 L reactor was stirred (˜200 rpm) at 60±5° C. for 28 hours. Upon work-up, 2000 g of lauryl lactate (80% yield) was obtained as a pale yellow liquid. The purity of the product was >97% as assessed by GC.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].N1C=CC=CC=1.[Cl-].[C:20]([O:27][CH2:28][CH:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][CH3:33])(=[O:26])/[CH:21]=[CH:22]\[C:23]([O-])=[O:24].C(OCC)(=O)C>C(#N)C>[C:20]([O:27][CH2:28][CH:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][CH3:33])(=[O:26])/[CH:21]=[CH:22]\[C:23]([O:4][CH2:3][C:2]([F:12])([F:1])[C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9])=[O:24]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCC(CC)COC(=O)/C=C\C(=O)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCC(CC)COC(=O)/C=C\C(=O)OCC(F)(F)C(F)(F)C(F)(F)F
Temperature: 20 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
2,2,3,3,4,4,4-Heptafluorobutanol (66.8 g, 0.334 mol) and pyridine (29.6 mL, 0.367 mol) were dissolved in acetonitrile (180 mL) and added with mono(2-ethylhexyl) maleate chloride (90.6 g, 0.367 mol), while-the internal temperature was maintained at 20° C. or lower on an ice bath. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour and added with ethyl acetate (1000 mL). The organic phase was washed with 1 mol/L aqueous hydrochloric acid and a saturated sodium chloride aqueous solution. Then, the organic phase was collected, the organic solvent was evaporated under reduced pressure, and residue was purified by silica gel column chromatography (hexane/chloroform=10/0 to 7/3 (v/v)) to obtain the target compound (80.3 g, yield: 59%) as a colorless transparent oily compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[C:2]1=[O:11].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl>[N:12]1[CH:17]=[CH:16][C:15]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:10])[C:2]2=[O:11])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1C(=O)N(c2ccncc2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1H-indole-2,3-dione (isatin, 552 mg, 3.75 mmol), pyridine-4-boronic acid (922 mg, 7.5 mmol), anhyd cupric acetate (1.36 mg, 7.5 mmol), activated 4A molecular sieve (2.0 g), triethylamine (1.05 mL, 7.5 mmol), pyridine (607 μL, 7.5 mmol) and dichloromethane (50 mL) is stirred for 24 hr at room temperature. The mixture is filtered through a pad of hyflo and evaporated. The residue is stirred with ethyl acetate, the insoluble copper salts removed by filtration and the filtrate is evaporated. The residue is purified by flash chromatography eluting with pentne-30 to 80% ethyl acetate to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]1[C:22]2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=[C:18]([NH2:25])[C:17]=2[N:16]=[C:15]1[CH3:26]>>[NH2:25][C:18]1[C:17]2[N:16]=[C:15]([CH3:26])[N:14]([CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:22]=2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCOCCNS(=O)(=O)N(C)C)c2c1C

Procedure:
Using the method of Examples 34–50, dimethylsulfamoyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5 -c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 371.1861.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([S:22][CH2:23][C:24](O)=[O:25])(=[O:21])[CH3:20].C(Cl)CCl.O>ClCCl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:25])[CH2:23][S:22][C:19](=[O:21])[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)SCC(=O)O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CC(=O)SCC(=O)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
2.94 g of 3-{3-(piperidinomethyl)phenoxy}propylamine was dissolved in 80 ml of dichloromethane, and stirred under cooling in an ice bath. 1.60 g of 2-(acetylthio)acetic acid and 2.26 g of EDC were added to this solution, and stirred at 0° C. for 30 minutes then at room temperature overnight. 100 ml of water and 50 ml of dichloromethane were added to the reaction solution, and extraction was carried out. The dichloromethane layer was washed twice with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography using methanol:dichloromethane=1:15 as developing solvent to obtain the colorless oily N-[3-{3-(piperidinomethyl)phenoxy}propyl]-2-(acetylthio)acetamide. Yield: 2.23 g.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].O=[C:15]([C:26](=[O:75])[NH:27][C:28]1[CH:29]=[N:30][N:31]([CH2:53][CH2:54][O:55][C:56]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:32]=1[NH:33][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].O>O1CCCC1>[C:1](/[CH:3]=[C:15](/[C:26]([NH:27][C:28]1[CH:29]=[N:30][N:31]([CH2:53][CH2:54][O:55][C:56]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:32]=1[NH:33][C:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:75])\[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)NCCC(=O)C(=O)Nc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC/C(=C\C#N)C(=O)Nc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.3 %

Procedure:
To a stirred solution of diethyl (cyanomethyl)phosphonate (311 mg) in tetrahydrofuran (13 ml) was added sodium hydride (70.3 mg, 60% oil suspension) under nitrogen atmosphere at 0° C., and the mixture was stirred for 45 minutes with warming to room temperature. tert-Butyl [3,4-dioxo-4-({5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazol-4-yl}amino)butyl]carbamate (1.32 g) was added to the mixture and the stirring was continued for 30 minutes. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave tert-butyl {(3E)-4-cyano-3-[({5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazol-4-yl}amino)carbonyl]-3-buten-1-yl}carbamate (1.13 g).
Reaction SMILES: [NH2:1][C@H:2]([CH2:33][O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:3][CH2:4][C:5]1[C:10]([NH:11][C:12](=[O:32])[C@H:13]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=CN=1.[S:52]1[C:56]2[CH:57]=[C:58]([S:61](Cl)(=[O:63])=[O:62])[CH:59]=[CH:60][C:55]=2[N:54]=[CH:53]1.[N+]([C:68]1C=CC(S(Cl)(=O)=O)=C[CH:69]=1)([O-])=O>>[S:52]1[C:56]2[CH:57]=[C:58]([S:61]([NH:1][C@H:2]([CH2:33][O:34][Si:35]([C:48]([CH3:49])([CH3:51])[CH3:50])([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:3][CH2:4][C:5]3[CH:69]=[CH:68][CH:8]=[CH:9][C:10]=3[NH:11][C:12](=[O:32])[C@H:13]([CH:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:14][C:15]([O:17][CH3:18])=[O:16])(=[O:63])=[O:62])[CH:59]=[CH:60][C:55]=2[N:54]=[CH:53]1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)N[C@H](C(=O)Nc1cccnc1CC[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(c1ccccc1)c1ccccc1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NS(=O)(=O)c1ccc2ncsc2c1)C(c1ccccc1)c1ccccc1
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from intermediate 34 following the procedure described for the step 8 in scheme I corresponding to the synthesis of example 1 but using 1,3-benzothiazole-6-sulfonyl chloride instead 4-nitrobenzene sulfonyl chloride MS: m/z=898.3 (MH+).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH:33]=[CH:34][C:35]#[N:36])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C([N:39](CC)CC)C>C([O-])(=O)C.CC(C)=O>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:39][C:28]2[CH:29]=[CH:24][CH:25]=[CH:26][C:27]=2[S:30]([CH:33]=[CH:34][C:35]#[N:36])(=[O:32])=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2ccccc2S(=O)(=O)C=CC#N)cc1
Reaction time: 8 h

Procedure:
6.9 grams (0.02 mol) of 4-dodecylbenzenesulfonyl chloride dissolved in 100 ml acetate are added, at room temperature, to a stirred solution of 3-(4-aminobenzenesulfonyl)acrylonitrile (4.2 g, 0.02 mol) and 3ml (0.02 mol) of triethylamine in 150 ml acetone. The mixture is permitted to stand overnight. 3-[(4-dodecylbenzenesulfonamido)benzenesulfonyl]acrylonitrile is recovered as a soft, fine yellow powder: ##SPC17##
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH:18]([C:39]([O:41]C)=[O:40])[NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)=[O:21])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.O.[OH-].[Li+]>O1CCCC1.CO.O>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH:18]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)=[O:21])[C:39]([OH:41])=[O:40])=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)C(Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1ccc2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.5 %

Procedure:
A solution of 5-(2-methoxycarbonyl-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-ethyl)-indazole-1-carboxylic acid tert-butyl ester (168 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL) in methanol (5 mL) was cooled to 0° C. A solution of lithium hydroxide monohydrate (49 mg, 2.04 mmol) in water (5 mL) was added. The reaction mixture was stirred at 0° C. for 6 h and then placed in the freezer for a further 16 h. The solvents were removed in vacuo and the residue dissolved in water (15 mL). The pH of the aqueous solution was adjusted to ca. 1 with 1N hydrochloric acid. The resulting white solid precipitated was collected by filtration. The solid was dried under vacuum to give the title compound (108 mg, 80%). 1H-NMR (DMSO-d6, 300 MHz) δ 12.94 (bs, 1H), 9.19 (s, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.28 (dd, J=8.5, 1.5 Hz, 1H), 7.13–7.06 (m, 2H), 6.86 (t, J=7.0 Hz, 1H), 6.76–6.72 (m, 2H), 4.32–4.24 (m, 2H), 4.09–4.02 (m, 4H), 3.17–2.97 (m, 2H), 2.72–2.59 (m, 2H), 1.57–1.35 (m, 4H). IR (KBr, cm−1) 3424, 2963, 2930, 1660, 1628, 1505, 1474, 1446, 753. Mass spec.: 463 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].[OH-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>CO.O1CCCC1.O>[CH2:25]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl

Procedure:
In a mixed solvent of methanol and tetrahydrofuran was dissolved 5.17 g of 4-hydroxy-3-chlorobenzoic acid, and a solution of 2.4 g of sodium hydroxide in 5 ml of water was added to the solution. Then, 10 ml of n-dodecyl bromide was added dropwise to the mixture and the resulting mixture was refluxed for 2 hours. Then, 1.2 g of sodium hydroxide was further added and the mixture was refluxed for 1 hour. The thus-obtained solution was put in a 1N aqueous solution of hydrochloric acid, and the precipitate was recovered and filtration, washed with water and then with n-hexane and recrystallized from ethyl acetate to obtain 4.1 g of 4-n-dodecyloxy-3-chlorobenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21].I[CH2:24][CH2:25][CH3:26]>>[CH3:13][C:8]1([CH3:12])[CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:24][CH2:25][CH3:26])=[C:3]([C:20](=[O:22])[CH3:21])[CH:4]=2)[O:9]1
Reactant: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2c1ccccc1
Reactant: CCCI
Product: CCCOc1cc2c(cc1C(C)=O)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure A, 1-(7-hydroxy-2,2-dimethyl-4-phenyl-2H-chromen-6-yl)-ethanone (Compound 61, 170 mg, 0.51 mmol) and 1-iodopropane (0.30 mL, 2.55 mmol) were reacted to produce the title compound as a colorless oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C@@:15]1([C:42]([F:45])([F:44])[F:43])[CH2:39][C@H:19]2[CH2:20][CH2:21][CH2:22][C:23]3[C:24](=[CH:25][C:26]4[CH:27]=[N:28][N:29]([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[C:30]=4[CH:31]=3)[C@:18]2([C:40]#[N:41])[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC.C1COCC1>[CH2:7]([O:14][C@@:15]1([C:42]([F:44])([F:45])[F:43])[CH2:39][C@H:19]2[CH2:20][CH2:21][CH2:22][C:23]3[C:24](=[CH:25][C:26]4[CH:27]=[N:28][N:29]([C:32]5[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=5)[C:30]=4[CH:31]=3)[C@:18]2([CH2:40][NH2:41])[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 0 °C

Procedure:
A suspension of LAH (38.0 mg, 1.00 mmol) in ether (1 mL) was stirred under nitrogen and cooled to 0° C. A solution of (3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (33, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rx=Benzyl) (89 mg, 0.167 mmol) in THF (3 mL) was added maintaining reaction temperature under 5° C. and the mixture was allowed to stir at rt for about 54 h. The reaction was diluted with THF (2 mL) and quenched by addition of water (40 μL), then 2N NaOH (40 μL) and then water (80 μL). The reaction was stirred overnight at rt. The mixture was dried with Na2SO4 and filtered through Celite®, rinsing with THF (5 mL) and EtOAc (10 mL). The combined organics were concentrated under reduced pressure to yield crude ((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methanamine (34, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rx=Benzyl). LC/MS, method 3, Rt=2.41 min, MS m/z 538 (M+H)+. The residue was used in step #3 without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][C@@H:6]1[CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][C@H:7]1[OH:18].CCl.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:2][C:3]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][C@@H:6]1[CH2:10][N:9]([C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[CH2:8][C@H:7]1[OH:18]
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1cccc(Cl)c1Cl
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCl
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](Oc2cccc(Cl)c2Cl)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 8.5 g (0.023 mole) of trans-4-(2,3-dichlorophenoxy)-1-phenylmethyl-3-pyrrolidinol hydrochloride and 100 liters of methyl chloride was cooled and treated dropwise with a solution of 23 g (0.125 mole) of benzylchloroformate in 100 ml of methylene chloride. The mixture was stirred at ambient temperature for 48 hr and then washed successively with water, 2N hydrochloric acid, 5% sodium hydroxide and water. The methylene chloride layer was dried over anhydrous sodium sulfate and then subjected to vacuum distillation at 100°/1.0 mm. to remove the methylene chloride, excess benzylchloroformate and benzyl chloride. An NMR analysis of the pot residue indicated only the oxygen was substituted. An additional 25 ml. of benzylchloroformate and 100 ml. of methylene chloride was added to the residue and the solution stirred at ambient temperature for 48 hr. The mixture was purified as above to give 14.6 g. of residue which was chromatographed on 300 g. of silica gel. The chromatography gave 5.6 g. of the disubstituted compound (See Example 20) and 1.0 g. of the titled compound as a white solid, m.p. 130°-2° C. (recrystallized from benzene).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]([NH2:40])([CH2:38][CH3:39])[CH3:37].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:36]([NH:40][C:28]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:8][C:2]=1[Cl:1])=[O:34])([CH2:38][CH3:39])[CH3:37]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CCC(C)N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (45 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, sec-butylamine (23 1l) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 34 mg (yield 52%) of the title compound.