Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([O:1][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: ClCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)c(OCCCN2CCOCC2)c1
Yield: 65.8 %

Procedure:
2-Hydroxy-4-methoxybenzaldehyde (25 g) in 125 ml of dimethylformamide is treated first with 8.2 g of 50% sodium hydride, then with 36 g of N-(3-chloropropyl)morpholine dissolved in 65 ml of toluene, following the procedure described in Example 1A, yielding 30.2 g of the title compound, boiling point 190°-195° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH4-].[Na+].[OH-].[Na+]>>[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:10][C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1ccc(CNc2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (2.66 g; 20 mmol; 1 eq.), 4-dimethylaminobenzaldehyd (3.28 g; 22 mmol; 1.1 eq.), NaBH4 (1.14 g; 30 mmol; 1.5 eq.) and 5 N NaOH (20 ml; 100 mmol; 5 eq.) according to method 2; Yield: 3.24 g (61.0%); MS m/z: 166.3; 1H-NMR (500 MHz, DMSO d6): δ 2.83 (s, 6H); 4.13 (s, 2H); 5.83 (br s, 1H); 6.53 (br s, 1H); 6.60 (dd, 1H, 4J=2.1 Hz, 3J=8.5 Hz); 6.66-6.68 (m, 2H); 7.17-7.20 (m, 2H); 7.25-7.26 (m, 1H); 7.83 (s, 1H); 11.86 (br s, 1H)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([S:40]([CH3:43])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:37][CH:38]=1)[S:40]([CH3:43])(=[O:42])=[O:41]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N(CCN(C)C)S(C)(=O)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [CH2:1]([S:5]([N:8](S(CCCC)(=O)=O)[C:9]1[CH:29]=[CH:28][C:12]2[O:13][C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:22]1([C:14]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:13][C:12]3[CH:28]=[CH:29][C:9]([NH:8][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])=[CH:10][C:11]=3[O:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCS(=O)(=O)N(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)S(=O)(=O)CCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)Nc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
N,N-Bis(butylsulfonyl)-2,2-diphenyl-1,3-benzodioxol-5-amine (Example 80, 79 mg, 0.15 mmol) was dissolved in tetrahydrofuran (4 ml). Tetrabutylammonium fluoride solution in tetrahydrofuran (1M, 0.16 mL, 0.16 mmol) was added dropwise at room temperature and the solution was stirred at room temperature overnight. The reaction was heated to reflux for 30 minutes, poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane as the eluant. Crystallization from hexane yielded the product as white crystals (45 mg, 74%).
Reaction SMILES: [C:1]1([C@@:7]23[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](#[N:23])[CH:21]=[CH2:22].[ClH:24]>CCOCC>[ClH:24].[C:20]([CH2:21][CH2:22][N:10]1[CH2:11][CH2:12][C@:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C@@H:8]2[CH2:9]1)#[N:23]
Reactant: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Reactant: C=CC#N
Agent: Cl
Solvent: CCOCC
Product: N#CCCN1CC[C@]2(c3ccccc3)Oc3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A 10 ml round bottom flask was charged with 0.503 g of cis 1,2,3,4,4a,9b-hexahydro-4a-phenyl-benzofuro[3,2-c]pyridine followed by 1 ml of acrylonitrile. The resulting mixture was stirred for 1/2 hour at room temperature under nitrogen and then heated at 60° for 1 hour. The reaction mixture was diluted with 10 ml of ether and treated with 4 ml of ether saturated with HCl. After stirring for 15 minutes, the precipitated salt was filtered, washed with ether, and dried to give 0.68 g (99.8%) of crystalline solid, m.p. s 205, 213°-216°. Recrystallization from ethanol afforded 0.50 g (73.3%) of crystals, m.p. s 213, 216°-219°.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[NH:24][CH2:23][C:22](=[O:25])[NH:21][N:20]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+].ClCCl>CO>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[NH:24][CH2:23][C:22](=[O:25])[NH:21][N:20]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CN3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CN3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(4,5-dihydro-1,2,4-triazin-6(1H)-one-3-yl)pyridinium bromide (300 mg, 0.74 mmol) was dissolved in methanol (8 ml), gradually added with sodium borohydride (280 mg, 7.4 mmol) under ice cooling and stirred at room temperature overnight. The solvent was removedunder reduced pressure. The residue obtained was added with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain the titled compound (165 mg) ascolorless plates.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19](OC(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:18][CH2:17]2)=[O:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].CC(C(O)=O)(C1C=CC(C(CCCN2CCC([O:56][CH:57]([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)CC2)=O)=CC=1)C>CS(C)=O>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:12])[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:57]([OH:56])([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:18][CH2:17]2)=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)CCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
To prepare the 10 mM stock solution of PS1, 1 mg of PS1 having a molecular weight of 618.8 was added to 162 μl of DMSO. For preparing the 50 mM stock solution of ebastine, 10 mg of ebastine having a molecular weight of 469.66 was added to 426 μl of DMSO. In preparing the 25 mM solution of carebastine, 1 mg of carebastine having a molecular weight of 499.65 was added to 80μ of DMSO. To obtain the 50 mM terfenadine stock solution 1.5 mg of terfenadine having a molecular weight of 471.7 was added to 64 μl of ETOH. To prepare the 50 mM stock solution of fexofenadine, 10 mg of fexofenadine chloride having a molecular weight of 538.12 was added to 372 μl of DMSO. Further, to prepare the 50 mM stock solution of astemizole, 10 mg of astemizole having a molecular weight of 458.57 was added to 436 μl of DMSO. Table 10 then lists the preparation of the solutions for use in the tests above.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=1)[CH2:2][CH3:3].C1C(=O)N([Cl:20])C(=O)C1>CC#N>[Cl:20][C:5]1[C:6]([C:9]([F:11])([F:12])[F:10])=[N:7][NH:8][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1cc(C(F)(F)F)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCCc1[nH]nc(C(F)(F)F)c1Cl

Procedure:
Following protocol L, 5-propyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in CH3CN to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[C:7]([C:20](OCC)=[O:21])=[CH:6]2.CC(C)(C)C([O:31][CH2:32][C:33]1[S:34][C:35]2[C:40]([N:41]=1)=[CH:39][C:38]([NH2:42])=[CH:37][N:36]=2)=O.C[Al](C)C>C1(C)C=CC=CC=1.Cl>[OH:31][CH2:32][C:33]1[S:34][C:35]2[C:40]([N:41]=1)=[CH:39][C:38]([NH:42][C:20]([C:7]1[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[C:9]3[C:5]([CH:6]=1)=[CH:4][C:3]([C:2]([F:1])([F:26])[F:25])=[CH:11][CH:10]=3)=[O:21])=[CH:37][N:36]=2
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(C)c1
Reactant: CC(C)(C)C(=O)OCc1nc2cc(N)cnc2s1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(Cn2c(C(=O)Nc3cnc4sc(CO)nc4c3)cc3cc(C(F)(F)F)ccc32)c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 39.8 %

Procedure:
To a solution of 150 mg (0.415 mmol) of ethyl 5-trifluoromethyl-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxylate prepared according to the protocol described in the preceding step and 132 mg (0.498 mmol) of (6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl 2,2-dimethylpropanoate, obtained in step 4.2, in 1.5 mL of dry toluene, maintained under an inert atmosphere, is added dropwise, at 0° C., 0.31 mL (0.623 mmol) of a trimethylaluminium solution (2M/toluene). The reaction mixture is stirred at 110° C. for 15 hours and then concentrated to dryness. The crude reaction product is then diluted with normal hydrochloric acid solution. The product is extracted with ethyl acetate and then purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate, to give 82 mg of the expected product.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20]1=[O:32].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][P:4]([NH:18][C@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20]1=[O:32])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Reactant: CCOC(=O)CN1CCCCC(N)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCCC[C@H](NP(=O)(CCCCc2ccccc2)OCC)C1=O
Reaction time: 0.33 h

Procedure:
A mixture of ethoxy(4-phenylbutyl)phosphinyl chloride [4.4 mmole; prepared as set forth in Example 1(f)], dry tetrahydrofuran (10 ml.), and 3-amino-2-oxo-hexahydro-1H-azepine-1-acetic acid, ethyl ester, monohydrochloride (1.0 g., 4.0 mmole) at 0° (ice bath) in an argon atmosphere is treated dropwise with triethylamine (1.7 ml., 3.0 eq.) in tetrahydrofuran (5 ml.) over 2 minutes. After 20 minutes, the ice bath is removed and the reaction mixture is stirred for an additional 1.5 hours. The reaction mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, and brine, dried (MgSO4) and evaporated. The residue (2.1 g.) is chromatographed on silica (65 g.) eluting with ethyl acetate then acetone to give 1.0 g. of (S)-hexahydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-2-oxo-1H-azepine-1-acetic acid, ethyl ester as an oil after evaporation. TLC (ethyl acetate) single spot at Rf =0.1.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:17]([CH3:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)cnc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (185 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (257 mg, 1.0 mmol, Amine-3) in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: [CH:1]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:21][O:22][C:23]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>C(O)C.C1COCC1>[CH3:21][O:22][C:23]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][C:1]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(CBr)c1OC
Reactant: CCOC(=O)C1CCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cccc(OC)c2OC)CCCCCC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of ethyl cycloheptane carboxylate (14 g, 82.4 mmol, prepared by esterification of the acid, which was obtained from Aldrich, by refluxing in ethanol in the presence of an acid catalyst), in 600 mL anhydrous THF cooled to -78° C. was added 60 mL of 1.5M LDA (monotetrahydrofuran in hexane, Aldrich) via syringe. The resulting light yellow reaction solution was stirred at -78° C. for 45 min and the benzyl bromide (from step A above) was added (19 g dissolved in 75 mL of THF, 82.4 mmol). The reaction was stirred at -78° C. for 4 hours, then it was quenched by addition of sat'd. NH4Cl, water and ether. The layers were separated, and the organic layer was washed with 1M HCl, water, and brine. The organic layer was dried over MgSO4, filtered, and evaporated to yield a light amber oil (28 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:29])[NH:12][C:13]1[C:14]([CH3:28])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26]O)=[CH:20][CH:19]=1)[CH3:9].[NH:30]1[CH:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[N:32]=[CH:31]1>>[CH3:38][O:37][C:35]([C:33]1[N:32]=[CH:31][N:30]([CH2:26][C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:28])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:29])=[CH:19][CH:20]=2)[CH:34]=1)=[O:36]
Reactant: Cc1noc(-c2ccc(C#CCO)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: COC(=O)c1c[nH]cn1
Product: COC(=O)c1cn(CC#Cc2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cn1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: {5-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-3-methyl-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester and methyl 4-imidazolecarboxylate.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:5]=1[O:6][C@@H:7]([CH3:12])[C:8]([O:10]C)=[O:9].Cl>C(O)C>[Cl:3][C:4]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:5]=1[O:6][C@@H:7]([CH3:12])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)[C@H](C)Oc1cc(OC)c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(O[C@@H](C)C(=O)O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97.8 %

Procedure:
125 ml (0.125 mol) of 1M sodium hydroxide solution were added to a solution of 34.9 g (0.125 mol) of methyl (S)-2-(2,4-dichloro-5-methoxyphenoxy)-propionate in 200 ml of ethanol. The solution was stirred at room temperature for 40 minutes and then adjusted to pH 1 with 2M hydrochloric acid. Most of the solvent was evaporated and the residue was partitioned between 400 ml of ethyl acetate and 400 ml of water. The separated organic phase was dried over anhydrous magnesium sulphate and evaporated to give 32.4 g (97.7%) of (S)-2-(2,4-dichloro-5-methoxyphenoxy)-propionic acid as a white solid, m.p. 114°-115° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[CH3:33])[NH2:29])(=[O:24])[CH3:23]>CC(O)C>[C:22]([O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[CH3:33])[NH:29][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Oc1cc(N)ccc1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (2.18 g, 7.25 mmol), 3-acetoxy-4-methylaniline (1.32 g, 8 mmol) and 2-propanol (50 ml) was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature. The precipitate was collected by filtration, washed with 2-propanol and ether to give 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline. A mixture of 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline (2.68 g, 5.75 mmol), 10% palladium-on-charcoal catalyst (0.27 g) in methanol (50 ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at ambient temperature under 1.5 atmospheres of hydrogen for 30 minutes. The catalyst was removed by filtration and the filtrate evaporated. The residual solid was triturated in ether, collected by filtration and dried under vacuum at 50° C. to give 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (2.1 g, 100%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al].Cl[CH:21](Cl)[CH2:22][Si:23]([Cl:26])([Cl:25])[Cl:24]>C(=S)=S.CCCCCC>[Cl:24][Si:23]([CH2:22][CH:21]1[C:12]2[CH:11]=[CH:10][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][C:7]=2[C:1]2[C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2)([Cl:26])[Cl:25]
Reactant: ClC(Cl)C[Si](Cl)(Cl)Cl
Reactant: c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Agent: [Al]
Solvent: S=C=S
Solvent: CCCCCC
Product: Cl[Si](Cl)(Cl)CC1c2ccccc2-c2cc(-c3ccccc3)ccc21
Yield: 15 %

Procedure:
In the same apparatus and procedures as Example 1 above, 5.0 g (21.7 mmol) of meta-terphenyl and 0.47 g (17.4 mmol) of aluminum foil were alkylated in CS2 (50 ml) solution with (2,2-dichloroethyl)-trichlorosilane 6.68 g (21.7 mmol) under dry nitrogen atmospheric pressure for 24 hr at reflux temperature. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and CS2 were distilled, recrystallization from ether yielded 1.27 g of 9-(trichlorosilyl)methyl-3-phenylfluorene (yield; 15%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NCCCCC1c1cccc(O)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCCCC1c1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A solution of 3-(3-hydroxyphenyl)hexahydro-2H-azepin-2-one (2.05 g) in dry DMF was added dropwise to a suspension of sodium hydride (0.3 g). After 30 minutes at ambient temperature, benzyl chloride (1.3 g) was added. The mixture was stirred for a further 2 hours and then cooled, and treated with water. The resulting solution was extracted several times with toluene, and the combined toluene layers washed thoroughly with water. The solvent was evaporated to give an oil that crystallised from ethyl acetate to give the title compound as a white solid (1.4 g) m.p. 119°-122° C.
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]([O-])(=[O:23])[CH2:14]CCC=CCCCC>>[C:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:23])[CH3:14]
Reactant: CCCCC=CCCCC(=O)[O-]
Reactant: CCCCC=CCCCC(=O)O
Product: CCCCC=CCCCCOC(C)=O

Procedure:
For example, 5-hexenoic acid or an ester of 5-hexenoic acid (e.g. methyl 5-hexenoate, ethyl 5-hexenoate, etc . . . ) could be used instead of 1-hexene, but the synthesis would entail a reduction of a carboxylic acid or an ester to an alcohol followed by acetylation. These syntheses are respectively shown in FIGS. 12 and 13. With reference to FIGS. 12 and 13, the 5-hexenoic acid or 5-hexenoate is reacted with 5-decene to form 5-decenoic acid or 5-decenoate, respectively, in the presence of Catalyst 823 and under vacuum. The resulting 5-decenoic acid or 5-decenoate is reduced and acetylated to form 5-decenyl acetate. In addition, synthesizing 5-decenoic acid has advantages because the salt of 5-decenoic acid can be recrystallized to increase the trans-isomer to greater than 90 percent trans-5-decenoic acid, which is then reduced and acetylated to greater than 90 percent trans-5-decenyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:5]([C:6]([O:8]C)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[O:16][CH3:17].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[O:16][CH3:17]
Reactant: COC(=O)c1c(Cl)cc(Cl)c(OC)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Yield: 94.1 %

Procedure:
To the methyl ester 2-2 (9.90 g, 35.3 mmol) in MeOH (150 mL) was added 2N NaOH (150 mL) and the reaction was heated to reflux for 2.5 h. Methanol was removed in vacuo and the mixture was extracted with EtOAc. The aqueous layer was acidified to pH 2 with a concentrated solution of HCl and then extracted into EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to provide the acid 2-1 as an orange solid (8.84 g, 94% yield). 1H NMR (400 MHz, d6-DMSO) δ 3.83 (s, 3H), 3.95 (s, 3H), 8.23 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH2:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42]>>[OH:43][CH:40]([CH2:41][OH:42])[CH2:39][NH:38][C:21]([N:11]1[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)([CH3:13])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([CH3:37])[N:9]=[C:10]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][C:25]=1[O:34][CH2:35][CH3:36])=[O:22]
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NCC(O)CO
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)NCC(O)CO

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-amino-propane-1,2-diol (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C30H31N3O4F3Cl2 [(M+H)+] 624.1638, observed 624.1641.