Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[CH3:17].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].[Cl-].[Li+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[CH3:17][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
2-Bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (0.10 g), 3-formylphenylboronic acid (0.05 g, 1.05 eq), lithium chloride (0.026 g, 2.0 eq), palladium acetate (1.4 mg, 2 mol %) and tri-tert-butylphosphonium tetrafluoroborate (1.8 mg, 2 mol %) were charged in a glass tube, and tetrahydrofuran (1 mL) and water (0.5 mL) were added thereto. After argon substitution, the mixture was stirred at 60° C. for 3 hr. The obtained reaction mixture was analyzed by high performance liquid chromatography to find the title compound (82.9% peak area).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:5]2.[NH:24](C(OC(C)(C)C)=O)[CH2:25][C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:13][CH2:14][N:15]([C:26](=[O:27])[CH2:25][NH2:24])[CH2:16][CH2:17]3)[CH:10]=1)[NH:7][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:5]2
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Clc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1
Product: NCC(=O)N1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
(5-Chloro-2-phenyl-1H-indol-7-yl)-piperidin-4-yl-amine prepared in Example 93 and N-BOC-Gly-OH were reacted according to the same procedure as Example 92 to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:7][P:8]([CH2:17][C:18]([CH3:35])=[CH:19][CH2:20][C:21]1[C:22]([OH:34])=[C:23]2[C:27](=[C:28]([CH3:32])[C:29]=1[O:30][CH3:31])[CH2:26][O:25][C:24]2=[O:33])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])C.[OH-].[Na+]>C1COCC1>[OH:34][C:22]1[C:21]([CH2:20][CH:19]=[C:18]([CH3:35])[CH2:17][P:8]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([O:7][CH:5]([CH3:6])[C:4]([OH:36])=[O:3])=[O:9])=[C:29]([O:30][CH3:31])[C:28]([CH3:32])=[C:27]2[C:23]=1[C:24](=[O:33])[O:25][CH2:26]2
Reactant: CCOC(=O)C(C)OP(=O)(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CP(=O)(Oc1ccccc1)OC(C)C(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 2-{[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionic acid ethyl ester (10 mg, 0.019 mmol) in THF (3 mL) was added 1N NaOH (232 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was dried under reduced pressure and the residue was purified by RP-HPLC to provide 6 mg (77%) of the desired product as a clear oil. 1H NMR (300 MHz, CD3OD) δ 1.41 (d, J=7 Hz, 3H), 1.97 (s, 3H), 2.16 (s, 3H), 2.59 (d, J=22 Hz, 2H), 3.45 (m, 2H), 3.79 (s, 3H), 4.83 (m, 1H), 5.26 (s, 2H), 5.43 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CD3OD) δ 27.02 ppm; MS (m/z) 413 [M−H]−, 415 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[O:23][CH2:22][CH2:21][O:20]2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC>[CH2:21]1[O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)([CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:4]3[N:3]=[C:2]([NH2:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=3)[CH2:31][CH2:32]2)[O:23][CH2:22]1
Reactant: Fc1ccc(C2(CCCN3CCNCC3)OCCO2)cc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Product: Nc1nc(N2CCN(CCCC3(c4ccc(F)cc4)OCCO3)CC2)ccc1[N+](=O)[O-]

Procedure:
5.6 g 2-amino-6-chloro-3-nitropyridine, 10 g 1-(3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-propyl)piperazine, 5 g potassium carbonate and 100 ml n-propanol are refluxed 21/2 hours. After cooling the precipitate is filtered off. The filtrate is concentrated to ca. 10 ml and diluted with the same volume of diisopropyl ether. The resulting cristallisate is admixed with the above mentioned precipitate and partitioned between water and methylene chloride. The organic phase is filtered and evaporated to give the heading compound, m.p. 117°-118°.
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH2:18])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH:18][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(N)ccc21
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
The title material from Example 17 step 6 (300 mg, 0.000767 mol) was dissolved in pyridine (5 mL), and to this solution was added methane sulfonyl chloride (88 mg, 0.000767 mol). The resulting solution was stirred at room temperature for 18 hours. The reaction was then concentrated in vacuo, and the resulting solids were triturated with water and the product was isolated by vacuum filtration. 88 mg. (MW=469.48, 25% yield). LC/MS m/z=470.3 (m+1).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[CH:37]=[C:36]3[C:32]([CH:33]=[N:34][NH:35]3)=[CH:31][CH:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([NH:28][S:25]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][CH:4]=[C:5]4[C:16]5[C:8](=[CH:9][CH:10]=[C:11]6[C:15]=5[S:14][CH:13]=[N:12]6)[NH:7][C:6]4=[O:17])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH:37]=2)[CH:33]=[N:34]1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3cn[nH]c3c2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2ccc3cn[nH]c3c2)cc1
Yield: 16 %

Procedure:
The title compound was prepared in 16% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(1H-indazol-6-yl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ12.9 (s, 1H), 11.1 (d, 1H), 10.9 (s, 1H), 10.4 (s, 1H), 9.3 (s, 1H), 8.1(d, 1H), 8.0 (s, 1H), 7.8 (d, 1H), 7.8 (d, 2H), 7.7 (d, 1H), 7.6 (d, 2H), 7.3 (s, 1H), 7.1 (d, 1H), 6.9 (d, 1H); APCI−MS m/z 487 (M−H)−.
Reaction SMILES: [C:1](/[C:4](=[CH:7]/N(C)C)/[C:5]#[N:6])(=O)[CH3:2].[C:11]([O:15][C:16]([NH:18][C:19]([NH2:21])=[NH:20])=[O:17])([CH3:14])([CH3:13])[CH3:12].CC1CCCO1>>[C:11]([O:15][C:16](=[O:17])[NH:18][C:19]1[N:21]=[C:1]([CH3:2])[C:4]([C:5]#[N:6])=[CH:7][N:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)/C(C#N)=C/N(C)C
Reactant: CC(C)(C)OC(=O)NC(=N)N
Solvent: CC1CCCO1
Product: Cc1nc(NC(=O)OC(C)(C)C)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 250 ml 3-neck flask was equipped with an overhead stirrer, thermocouple, reflux condenser and heating mantle. The flask was charged with (E)-2-acetyl-3-dimethylamino-acrylonitrile (8.93 g, 63.34 mmol), N-tert-butyloxycarbonyl-guanidine (10 g, 61.56 mmol) and 2-methyltetrahydrofuran (98.76 g). The resultant suspension was stirred and heated to reflux, whereupon the solids were observed to dissolve. The resultant mixture was stirred for about 6 hours, then concentrated by rotary evaporation to yield a solid which was triturated with water (120.00 g) to complete precipitation of the desired product. The resultant suspension was stirred for ˜30 minutes at ambient temperature, then filtered and the wet solid washed twice with water (120.00 g) and dried in a vacuum oven at 75-80° C. under a N2 bleed overnight to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1.[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:16]=1.C[Si](C#C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(N(CC)CC)C.C1COCC1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:15]([C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1)#[CH:16]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1cccc(OC2CCCOC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C#Cc1cccc(OC2CCCOC2)c1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a well degassed solution of 3-(3-bromophenoxy)tetrahydropyran (5.14 g), triphenylphosphine (204 mg), copper(I) iodide (38 mg) and bis(triphenylphosphine)palladium(II) dichloride (3.93 g) in triethylamine (40 ml), maintained under argon atmosphere, trimethylsilylacetylene is added and the mixture is stirred at 85° C. for 3 h. The precipitated ammonium salts was removed by filtration and the filtrate was evaporated to dryness. This affords a yellowish oil which is dissolved in 30 ml of THF containing 3 ml of water, then cooled at 0° C. and treated by dropwise addition of 5 ml of tetrabutylammonium fluoride (1M in THF). After stirring for 30 min the reaction was complete and the obtained brownish solution was filtered over a short silica-gel column and concentrated to yield a brownish residue, which was chromatographed on silica-gel column affording 3-(3-ethynylphenoxy)tetrahydropyran as yellowish crystals.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@@:20]1([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:49][C:44]1[CH:43]=[C:42]([C@@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=3)[CH2:21]2)[CH:47]=[CH:46][C:45]=1[Cl:48]
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (R)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[[3,5-bis(trifluoromethyl)phenyl]acetyl]pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: B.[CH3:2][O:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:8][C:7]=1[CH:16]1[CH2:21][CH2:20][CH2:19][C:18](=[N:22][OH:23])[CH2:17]1.C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:2][O:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:8][C:7]=1[CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][OH:23])[CH2:17]1
Reactant: COCOc1ccc(C2CCCC(=NO)C2)c(OCOC)c1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCOc1ccc(C2CCCC(NO)C2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Borane (0.412 ml of a 1M solution in tetrahydrofuran) was added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone oxime (85 mg) in tetrahydrofuran (2 ml) at 0° C. under argon. After 2 hr, acetic acid (1 ml) was added and the mixture was allowed to warm to ambient temperature. After 16 hr, sodium hydrogen carbonate (20 ml of a saturated aqueous solution) was added, the mixture was extracted with ethyl acetate (3×20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, dichloromethane/methanol, 9:1 v/v) to furnish two compounds as clear gums which were identified as diastereoisomers of the title compound; trans-isomer (12 mg, 14%) m/z (ES+) 312 (M+H)+; cis-isomer (0.017 g, 20%) m/z (ES+) 312 (M+H)+.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][CH:16]=[N:15][C:14]=2[N:13]([C@@H:21]2[O:36][C@H:35]([CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=3[Cl:47])[C@@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[C@@:22]2([CH3:48])[OH:23])[CH:12]=1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>C1COCC1.[Cl-].[Na+].O>[Cl:20][C:18]1[C:19]2[C:11]([CH2:10][CH2:9][OH:1])=[CH:12][N:13]([C@@H:21]3[O:36][C@H:35]([CH2:37][O:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=4[Cl:47])[C@@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[Cl:34])[C@@:22]3([CH3:48])[OH:23])[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(CCO)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
To a solution of compound 2.5 (1.14 g, 1.47 mmol) in THF (30 mL) was added a 1.0M solution of tetrabutylammonium fluoride in THF (2.2 mmol) at room temperature. The colorless solution was stirred for 5 hr at room temperature and then diluted by addition of 10 mL of CH2Cl2 and 10 mL of brine. The aqueous layer was extracted three times with CH2Cl2, dried over Na2SO4, filtered and evaporated. The residue obtained was purified by silica gel column chromatography using 1-1.5% MeOH in CH2Cl2 as eluent to give the desired compound 2.6 (900 mg, 88%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.Cl.[CH2:30]([OH:33])[CH2:31][OH:32]>C(OCC)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:3]2[C:4]([NH:8][S:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=3)(=[O:10])=[O:11])=[N:5][CH:6]=[N:7][C:2]=2[O:32][CH2:31][CH2:30][OH:33])=[CH:23][CH:24]=1
Reactant: O=S(=O)(Nc1ncnc(Cl)c1-c1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1
Reactant: OCCO
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ncnc(OCCO)c1-c1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
A solution of 0.046 g of Na in 1.5 ml of absolute ethylene glycol was treated with 0.216 g of N-[6-chloro-5-(p-chloro-phenyl)-4-pyrimidinyl]-α,α,α-trifluoro-p-toluenesulfonamide with the exclusion of moisture and heated at 100° C. for 3 hours, thereafter cooled to room temperature and treated with 2.3 ml of 1N HCl. The mixture was taken up in ethyl acetate, the organic extracts were washed with water, dried and evaporated under reduced pressure. The precipitate remaining behind was recrystallized from CH2Cl2, isopropyl ether and n-hexane and yielded N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-α,α,α-trifluoro-p-toluenesulfonamide, melting point 160°-162° C.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:30][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:6]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:5][N:4]=2)=[CH:27][CH:26]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1
Reactant: OCc1ccc(Cl)cc1
Product: Clc1ccc(COc2ncc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)n2)cc1

Procedure:
2-Methylthio-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 4-chlorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(4-chlorobenzyloxy)-4-(4-chloro-phenyl)-5-(2,4-dichlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=475 (M++1); Rt=5.01 min; 1H-NMR 400 MHz (CDCl3): 5.55 (s, 2H), 7.1 (d, J=9 Hz, 1H), 7.25-7.3 (m, 4H), 7.15-7.20 (m, 3H), 7.43 (m, 3H), 8.45 )s, 1H) and 2-(4-chlorobenzyloxy)-4-(4-chlorophenyl)5-(2-chloro-4-thiomethylphenyl)pyrimidine (LRf): HPLC/MS: m/e=487 (M++1); Rt=4.91 min; 1H-NMR 400 MHz (CDCl3): δ 2.52 (s, 3H), 5.55 (s, 2H), 7.15 (d, J=6 Hz, 2H), 7.25-7.30 (m, 3H), 7.55-7.40 (m, 4H), 7.45 (m, 2H), 8.42 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39])[C:32](O)=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([N+:38]([O-:40])=[O:39])=[C:29]([O:28][CH3:27])[CH:30]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
1.2 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.08 g of 3-methoxy-4-nitrobenzoic acid and 0.96 g of dicyclohexylcarbodiimide are dissolved in a mixture of 30 ml of methylene chloride and 8 ml of dimethylformamide under ice-cooling. A catalytic amount of 4-(dimethylamino)pyridine is added to the solution, and said mixture is stirred at room temperature overnight. After the reaction, the precipitates are removed by filtration. The filtrate is washed with an aqueous potassium carbonate solution and then with water, dried and evaporated to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:methanol=20:0.3). 1.2 g of (+)-cis-2-(4-methoxyphenyl)-3-(3-methoxy-4-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as an oil. Yield: 67.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccc(OC)cc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccc(OC)cc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(4-methoxyphenyl)benzoic acid (50 mg, 0.1184 mmol) and morpholine (21 mg, 0.2413 mmol) were dissolved in methylene chloride (30 ml), then WSC-HCl (68 mg, 0.3547 mmol) was added thereto and the mixture was stirred for 16 hours at room temperature. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (30 mg, 0.0613 mmol, 52%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[CH:5]2.[N:15]1([CH2:20][CH2:21]O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N+:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][CH2:21][CH2:20][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:11][CH:10]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccc(O)cc2c1
Reactant: OCCN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc2ccc(OCCN3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
6-Hydroxy-3-nitroquinoline (148 mg, 0.78 mmol) was dissolved in THF (18 mL). 2-(Pyrrolidin-1-yl)ethanol (0.091 mL, 0.78 mmol) and triphenylphosphine (306 mg, 1.17 mmol) were added. Lastly, diethyl azodicarboxylate (0.184 mL, 1.17 mmol) was added and the reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was then concentrated in vacuo and the residue was purified by flash chromatography (SiO2) to yield 134 mg (60%) of 3-nitro-6-(2-(pyrrolidin-1-yl)ethoxy)quinoline. LC/MS (m/z): 288.1 (MH+), Rt 1.80 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][CH3:19])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20]CCCl>>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][N:10]=1)[CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCCl
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cn1
Product: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(tert-Butoxycarbonyl-ethyl-amino)-nicotinic acid (6.40 g, 24.0 mmol) is taken up in 150 mL DCE, 1-chloro-N,N-2-trimethylpropenyl-amine (6.42 mL, 48.1 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is concentrated under reduced pressure and the crude product is used in the next step without purification.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:18](OC)=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.CO>C1COCC1>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:18][OH:19])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c2ccc(O)cc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(-c2ccccc2)c2ccc(O)cc2c1
Reaction time: 2 h

Procedure:
To a solution of 1-phenyl-3-carbomethoxy-6-naphthol (Naphthol 11) (2.5 g, 9 mmoL) in dry THF (50 mL) at 0° C. was added (4.8 mL, 2.7 mmoL, 3 eq.) of DIBAL-H. The resulting solution was stirred for 2 hr. Then methanol (excess) was added and the solvent evaporated. The mixture was diluted with EtOAc, washed successively with HCl, 1N, H2O, brine, to give the title compound.