Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[N:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[N+:3]=[N-:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:37]([O:41][C:42](=[O:60])[NH:43][CH2:44][CH2:45][CH2:46][O:47][C:48]1[C:57]2[CH2:56][CH2:55][CH2:54][CH2:53][C:52]=2[C:51]([CH:58]=O)=[CH:50][CH:49]=1)([CH3:40])([CH3:39])[CH3:38].O>C1COCC1>[C:37]([O:41][C:42](=[O:60])[NH:43][CH2:44][CH2:45][CH2:46][O:47][C:48]1[C:57]2[CH2:56][CH2:55][CH2:54][CH2:53][C:52]=2[C:51]([CH:58]=[CH:7][CH2:6][CH2:5][N:2]=[N+:3]=[N-:4])=[CH:50][CH:49]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: [N-]=[N+]=NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(C=O)c2c1CCCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(C=CCCN=[N+]=[N-])c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
(3-Azido-propyl)-triphenylphosphonium bromide (112, 11.5 g, 27 mmol) was stirred with 100 mL of dry THF at −76° C. LiHMDS (0.5 M in toluene, 27 mL) was added and the mixture was stirred for 30 minutes. [3-(4-Formyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester (111, 6 g, 18 mmol) in 12 mL dry THF solution was introduced. The reaction mixture was stirred at this temperature for another 30 minutes, and slowly warmed to room temperature. The mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, concentrated, and purified by flash chromatography (0-25% EtOAc/Hexane) to give 3.5 g 113 {3-[4-(4-azido-but-1-enyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-propyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnccn1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 95.1 %

Procedure:
A solution of 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (200 mg, 0.545 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (181 mg, 0.739 mmol), diisopropylethylamine (0.129 ml, 0.739 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and a solid was collected by filtration and washed with water. This was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (190 mg, 95.4%) as a solid. mp 134-135° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21]COC)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(O)cccc1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 41.5 %

Procedure:
Ethyl 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(methoxymethoxy)benzoate (Intermediate 177, 950 mg, 2.68 mmol) was dissolved in dichloromethane (30 ml), the solution was cooled to 0° C. and trifluoroacetic acid (2 ml) was added. After 3 h stirring at 0° C. water (20 ml) was added at 0° C. and two phases were separated. The organic layer was dried over Na2SO4 and evaporated in vacuo to afford a colourless oil that was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound (0.345 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13]O.C1C(=O)N([O:22][C:23]([O:25][N:26]2[C:31](=[O:32])[CH2:30][CH2:29][C:27]2=[O:28])=[O:24])C(=O)C1.C(N(CC)CC)C.C(OCC)(=O)C.CO>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:22][C:23](=[O:24])[O:25][N:26]1[C:27](=[O:28])[CH2:29][CH2:30][C:31]1=[O:32]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: COCCOCCOCCOCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCOCCOCCOCCOC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
Tetraethylene glycol monomethyl ether (1.0 g, 4.8 mmol) and N,N′-disuccinimidyl carbonate (1.48 g, 5.8 mmol) were dissolved in acetonitrile (10 mL). Then triethylamine (1.0 mL, 7.2 mmol) was added and the reaction stirred overnight at room temperature. Crude reaction was evaporated to dryness, dissolved in sat. NaHCO3 (30 mL), washed ethyl acetate (2×30 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate/MeOH, 20:1) afforded 1 a clear oil (0.462 g, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([CH3:8])[CH2:7][O:19]2)=[CH:4][CH:3]=1
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1(c2ccc(Cl)cc2)CO1
Yield: 52.4 %

Procedure:
To a stirred and cooled solution (0°-5° C.) of 4-chloro-α-methylstyrene (15.2g) in chloroform (350 mL), add m-chloroperbenzoic acid (21.6 g). Stir the reaction mixture for 1 hr by which time all starting material will haye reacted to give virtually a single product. Remove the m-chlorobenzoic acid formed by washing chloroform solution with aqueous NaHCO3 followed by water (150 mL). Dry the chloroform solution (Na2SO4) and evaporate to dryness to provide a colorless oil. Distill the oil in vacuo (1 mm) and collect fractions distilling between 65°-72° to give the title compound (8.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:17]2[CH:18]=[N:19][CH:20]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccncc1F
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cnccc2C(=O)O)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 4-methoxybenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.29 (d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=8.5 Hz), 4.47 (s, 2H), 3.73 (s, 3H). [M+H] calc'd for C14H14N2O3, 259. Found 259.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[Cl-].[Ca+2:7].[Cl-].CCC1(CC)C(=O)NC(=O)NC1=O>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:7].[Ca+2:7]
Reactant: O=P(O)(O)O
Agent: CCC1(CC)C(=O)NC(=O)NC1=O
Agent: [Ca+2]
Agent: [Cl-]
Product: O=P([O-])([O-])[O-]

Procedure:
This example demonstrates the use of the method of the present invention in a T-4 test based on dilution of labeled T-4 added to a test sample. Two T-4 controls having assigned or known T-4 values were employed. Serum Sample 1 contained 9.2 μgm % T-4, while Serum Sample 2 contained 15.6 μgm % T-4. 0.1 ml of the serum samples was placed in separate test tubes. To each was added 1 ml of a phosphoric acid solution of calcium chloride containing 36 mg of calcium chloride/ml and having a pH of 1.5. Following mixing, there was added to each tube 0.1 ml of a solution having the following composition: 5 ml of barbital buffer of ionic strength, 0.075, 10 μl of 10% albumin and 5 μCi of I125 labeled T-4. The solution had a pH of approximately 8.6. The resulting solution was mixed and there was then added 2.5 ml of a barbital buffer of ionic strength, 0.075, having a pH of 8.6. Upon addition of the barbital buffer and mixing, there was formed a solid adsorbent comprised of calcium phosphate, the final mixture having a pH of approximately 5. The serum samples were centrifuged and the solid adsorbent in each case counted using a scintillation counter. The results are shown below:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][C:4]([CH3:18])([CH3:17])[O:3]1.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-].Br[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][N:30]=1>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([C:6]2[CH2:7][C:2]([CH3:1])([CH3:19])[O:3][C:4]([CH3:17])([CH3:18])[CH:5]=2)=[N:30][CH:31]=1)([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)O1
Temperature: 80 °C
Yield: 83 %

Procedure:
2,2,6,6-Tetramethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (as prepared in the previous step) (18.5 g, 0.069 mol) was dissolved in dimethoxyethane (DME) (350 mL). The resulting solution was treated with 2 M Na2CO3 (280 mL, 0.560 mol), LiCl (5.00 g, 0.110 mol) and 2-bromo-5-nitropyridine (14.0 g, 0.060 mol). The resulting mixture was degassed by sonication for 30 min under Ar and then Pd(PPh3)4 (8.00 g, 6.90 mmol) was added and the reaction heated at 80° C. under Ar overnight. The reaction mixture was allowed to cool to RT and extracted with EtOAc (3×150 mL). The residue was purified on silica gel with 2-10% EtOAc:hexane to obtain the title compound as a pale yellow solid (15.2 g, 83%). 1H-NMR (CDCl3; 400 MHz): δ 9.40 (d, 1H, J=2.8 Hz), 8.45 (dd, 1H, J=8.8, 2.8 Hz), 7.59 (d, 1H, J=8.8 Hz), 6.90 (t, 1H, J=1.6 Hz), 2.5 (d, 1H, J=1.6 Hz), 1.40 (s, 6H), 1.34 (s, 6H).
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 73.9 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and isopropanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (4 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 10.8 g of p-cyanobenzamide (yield 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([SH:15])[N:10]=2)=[CH:5][CH:4]=1.[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][S:15][C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:14]=[CH:13][N:12]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2ccnc(S)n2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2nccc(-c3ccc(OC)cc3)n2)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-(4-methoxy-phenyl)-pyrimidine-2-thiol (225a) (1.00 g, 4.58 mmol) in DMF (30 mL) was added 4-bromomethyl-benzoic acid methyl ester (1.05 g, 4.58 mmol). The mixture was heated at 60° C. for 1 h and evaporated to dryness to form the compound 226a, which was used in the next without purification. LRMS=366.4 (calc.), 367.4 (found).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]2[O:9][CH2:8]2)=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[C:22]1([CH2:28][CH2:29][CH:30]([NH2:32])[CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]([OH:9])[CH2:8][NH:32][CH:30]([CH3:31])[CH2:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: COc1ccc(C2CO2)cc1OCCOC1CCCCO1
Reactant: CC(N)CCc1ccccc1
Solvent: CCO
Product: COc1ccc(C(O)CNC(C)CCc2ccccc2)cc1OCCOC1CCCCO1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 34.9 %

Procedure:
14.7 g of 4-methoxy-3-[2-(tetrahydro-2-pyranyloxy)ethoxy]styrene oxide was dissolved in 770 ml of ethanol, and 55 g of 4-phenyl-2-butylamine was added. The mixture was stirred at 90° C. for 40 minutes. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to afford 7.73 g (yield 34.9%) of 1-[4-methoxy-3-[2-(tetrahydro-2-pyranyloxy)ethoxy]phenyl]-2-(1-methyl-3-phenylpropyl)aminoethanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[O:7][CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[C:5]=2[CH:4]=1.S(OCCC)([C:32]1C=CC(C)=CC=1)(=O)=O.COC1C(N2CCNCC2)=NC=CC=1>>[ClH:2].[CH3:32][C:3]1[CH:28]=[CH:27][C:6]2[O:7][CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[C:5]=2[CH:4]=1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cccnc1N1CCN(CCCc2coc3ccc(Cl)cc23)CC1
Agent: COc1cccnc1N1CCNCC1
Agent: Cl
Product: COc1cccnc1N1CCN(CCCc2coc3ccc(C)cc23)CC1

Procedure:
The title compound was prepared (0.66 g, 92%, mp 163°-165° C.) in a manner analogous to the preparation of 1-[3-(5-chlorobenzo[b]furan-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)piperazine (Example 25) by the reaction of 5-methyl-3-benzo[b]furan)propanol tosylate with 1-(3-methoxy-2-pyridinyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:16]=2)[C:5]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.S(O)(C(F)(F)F)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=2)[C:5]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3NC3CCOCC3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2NC2CCOCC2)n1
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A solution of 4-(5-chloro-2-(tetrahydro-2H-pyran-4-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (190 mg, 0.339 mmol) in TFA (5000 μL, 64.9 mmol), and TfOH (100 μL, 1.126 mmol) was heated at 80° C. for 3 h. The mixture was concentrated and stirred with saturated NaHCO3 (10 mL) for 30 min. The suspension was filtered and washed with water (2×5 mL). The resulting solid was briefly rinsed with DCM (5 mL) and EtOAc (5 mL) to give the product as a yellow solid (68 mg). LCMS (ES, pos.): calcd for C14H17ClN6O: 320.1. found: 321.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 9.61 (d, J=7.24 Hz, 1H); 8.58 (d, J=2.15 Hz, 1H); 8.23 (d, J=2.15 Hz, 1H); 7.68 (d, J=17.41 Hz, 2H); 4.21 (br. s., 1H); 3.88 (d, J=11.54 Hz, 2H); 3.47 (t, J=10.66 Hz, 2H); 2.38 (s, 3H); 1.92 (d., J=11.932H); 1.64 (q, J=9.59 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[N:12]=[C:13]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:14]2[S:19][C:18]([CH:20]=O)=[CH:17][C:15]=2[N:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[Cl:10][C:11]1[N:12]=[C:13]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:14]2[S:19][C:18]([CH2:20][NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:17][C:15]=2[N:16]=1
Reactant: NCCN1CCOCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2sc(CNCCN3CCOCC3)cc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.7 %

Procedure:
To a solution of 4-(2-aminoethyl)-morpholine (600 mg) stirring in anhydrous 1,2-dichloroethane (40 ml), was added 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (1.31 g), followed by glacial acetic acid (277 μl) and sodium triacetoxy borohydride (1.27 g) added in several aliquots over 30 minutes. The reaction mixture was stirred for 12 hours at room temperature, then diluted with chloroform (50 ml), washed with 50% NaHCO3 solution and dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by flash silica chromatography to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-ylmethyl)-(2-morpholin-4-yl-ethyl)-amine (398 mg), as a white solid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CC.C(OC1C=CC(C2C=CC(C#N)=CC=2)=CC=1)CCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Product: CCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In the synthesis of 4'-octyloxybiphenyl-4-carboxylic acid of Example 12, the same hydrolysis as in Example 12 was repeated except hat 4'-hexyloxy-4-cyanobiphenyl was used instead of 4'-octyloxy-4-cyanobiphenyl to obtain 4'-hexyloxybiphenyl-4-carboxylic acid. This 4'-hexyloxybiphenyl-carboxylic acid was condensed with (+)-4-(2-methylnonanoyl) phenol in the same manner as in the synthesis of 4-(2-metylnonanoyl) phenyl, 4'-octyloxybiphenyl-4-carboxylic acid ester of Example 13 to synthesize 4-(2-methylnonanoyl) phenyl, 4'-hexyloxybiphenyl-4-carboxylic acid ester having the aforementioned physical and chemical properties.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:36][CH:35]([N:37]([CH3:39])[CH3:38])[CH2:34][C:33]2([CH3:41])[CH3:40])[N:3]=1>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:36][CH:35]([N:37]([CH3:39])[CH3:38])[CH2:34][C:33]2([CH3:41])[CH3:40])[N:3]=1
Reactant: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)C(C)(C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)C(C)(C)C1
Reaction time: 3.5 h

Procedure:
To a solution of [(2R)-3-(2-{2-chloro-6-[4-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (1.6493 g, 2.795 mmol) in MeOH (28 mL) was added 20% Pd(OH)2/C (50% water, 165 mg). The mixture was hydrogenated for 3.5 h, and then filtered. The solution was concentrated in vacuo, and the residue was purified by Gilson RPLC to provide [(2R)-3-(2-{2-chloro-6-[4-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (0.7580 g, 54%, single unknown diastereomer) as a pink solid following crystallization from EtOAc-hexanes. LCMS: (M+H)+: 500.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:41][C@@H:42]1[CH2:47][CH2:46][CH2:45][C@H:44]([OH:48])[CH2:43]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:14]([NH:41][C@@H:42]2[CH2:47][CH2:46][CH2:45][C@H:44]([OH:48])[CH2:43]2)=[O:16])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: O=C(O)c1noc(-c2ccc(Cl)cc2)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCC[C@H](O)C1)c1noc(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 18 mg (0.07 mmol) of 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylic acid in anhydrous N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 27 mg, 0.07 mmol), followed by (1S,3R)-3-aminocyclohexanol (8.1 mg, 0.07 mmol) with stirring at room temperature. After 18 h, the solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The aqueous layer was separated and repeatedly extracted with ethyl acetate, the combined organic extracts were dried (MgSO4), the solvent removed in vacuo and the residue was purified by preparative HPLC to afford the title compound: (5.3 mg, 0.015 mmol). MS (ESI) m/z (M+H+): 354.9/356.9.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[C:20]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O)([CH3:23])([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[C:20]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccccc1C=O
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (2 mL) was added a solution of triethylamine (0.35 mL) and 2-tert-butylbenzaldehyde (101 mg) in DMF (1 mL). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature overnight, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (92 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[CH:12][C:11]=2[N+:32]([O-:34])=[O:33])[O:7][C:6]=1[CH3:35])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO.CCOC(C)=O>[CH3:35][C:6]1[O:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[CH:12][C:11]=2[N+:32]([O-:34])=[O:33])=[CH:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(-c2ccc(NC(=O)Cc3cc(OC)c(OC)c(OC)c3)cc2[N+](=O)[O-])oc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)Nc2ccc(-c3cc(C(=O)O)c(C)o3)c([N+](=O)[O-])c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.4 %

Procedure:
Dissolve 2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylic acid methyl ester (59) (50 mg, 0.10 mmol) in THF (1.0 mL) and MeOH (0.5 mL) at rt and add 1M aqu LiOH (525 μL, 0.52 mmol). Stir the reaction mixture for 17 h at rt. Add dropwise 1M aqu. HCl (5804, 0.58 mmol) and extract the mixture with EtOAc (3 times), wash the combined organic layer with brine and dry it with Na2SO4. Purify the obtained crude product by preparative TLC (silica gel, EtOAc/MeOH 9+1) to obtain 2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylic acid (60) (35 mg, 71%) as a brown sticky solid. 1H NMR (400 MHz, CDCl3): 2.61 (s, 3H); 3.70 (s, 2H); 3.86 (s, 3H); 3.87 (s, 6H); 6.51 (s, 2H); 6.85 (s, 1H); 7.29 (br.s, 1H); 7.58 (d, 1H, J=8.6 Hz); 7.62 (dd, 1H, J1=9.0 Hz, J2=2.2 Hz); 7.98 (d, 1H, J=2.0 Hz).