Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](SC)[C:5]([C:12]#[N:13])=[C:4]([S:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[S:19][CH:20]=2)[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[Cl-].[NH4+].C(OCC)(=O)C>CC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:5]([C:12]#[N:13])=[C:4]([S:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[S:19][CH:20]=2)[N:3]=1
Reactant: C1CCNCC1
Reactant: CSc1c(C#N)c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c1C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1

Procedure:
5.00 g (11.63 mmol) of the compound from Example 44A and 57.50 ml (581.43 mmol) of piperidine were initially charged in 120 ml of acetone and heated at reflux for 8 h. After cooling, the mixture was poured into a solvent mixture of 50 ml of saturated aqueous ammonium chloride solution and 50 ml of ethyl acetate. The phases were separated. The organic phase was washed twice with in each case 20 ml of saturated aqueous sodium chloride solution and then dried over magnesium sulfate. After removal of the solvent, the residue was triturated with 100 ml of diethyl ether. The precipitate was filtered off with suction and dried under reduced pressure at 50° C.
Reaction SMILES: Br[CH:2]([CH:9]=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:11]([NH2:14])(=[S:13])[CH3:12]>ClC(Cl)C>[CH3:12][C:11]1[S:13][C:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][N:14]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)CC(Br)C=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cc1cnc(C)s1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
A mixture of 28.7 g of ethyl 3-bromo-4-oxo-butyrate, 300 ml of dichloroethane and 11.2 g of thioacetamide was refluxed for 10 hours with stirring while replacing the dichloroethane that distilled to keep the volume constant and then the mixture was cooled to room temperature. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. The solution was extracted with 2N hydrochloric acid and the pH of the aqueous extracts was made alkaline by addition of ammonium hydroxide. The mixture was extracted with ethyl acetate and the organic extract was washed with water, dried and evaporated to dryness to obtain 8.3 g of ethyl 2-methyl-5-thiazole acetate. The IR spectrum in CHCl3 showed ester C=O at 1737cm-1 and C=C and C=N at 1535cm-1.
Reaction SMILES: [B:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7](O)=[O:8])([OH:3])[OH:2].[CH3:15][NH:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:15][N:16]([CH3:17])[C:7]([C:6]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:4]([B:1]([OH:3])[OH:2])[CH:5]=1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)N(C)C)cc1B(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
To a solution of 700 mg (3.57 mmol) 3-borono-4-methoxybenzoic acid in 23 ml DMF, 3.6 ml (7.14 mmol) dimethylamine, 1.5 g (3.93 mmol) HATU and 1.57 ml (14.29 mmol) NMM were added and stirred at RT for 2 hours. The reaction mixture was extracted with EtOAc and water. The organic phase was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC (Prep. HPLC method 1, gradient: 15-30% in 16 minutes). The fractions containing product were combined and extracted twice with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated to afford 361 mg (1.619 mmol, 45.3% yield) of the title compound as a colorless solid. LCMS: (M+H)=224; tR=0.54 min (LC-MS 4). 1H-NMR (d6-DMSO, 400 MHz) δ ppm 7.56 (m, 1H) 7.44 (dd, 1H) 6.99 (d, 1H) 3.81 (s, 3H) 2.93 (s, 6H).
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][C:5]=1[CH3:16].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[S:13][CH:14]=2)=[CH:6][C:5]=1[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(-c2csc(N)n2)cc1C
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2csc(NS(=O)(=O)c3ccc(C)cc3)n2)cc1C

Procedure:
A mixture of 0.5 g of 4-(4-methoxy-3-methyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.5 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored solution was poured into 50 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a hot mixture of 20 ml of ethanol and 50 ml of water. 0.06 g of N-[4-(4-methoxy-3-methyl-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as beige crystals upon cooling.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:5][O:4]1.C(=O)(O)[O-].[Na+].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(#N)C>[CH2:11]([N:18]1[CH2:5][CH:3]([OH:4])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCC1CO1
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: OC1CN(Cc2ccccc2)C1

Procedure:
reacting (±)-2-(chloromethyl)oxirane, sodium bicarbonate and benzylamine at about 0° C. to about 80° C. in acetonitrile and water to provide 1-benzyl-3-azetidinol, reacting the 1-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 40° C., and isolating 1-benzyl-3-azetidinol (2E/Z)-2-butenedioate;
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC(N)CO
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CCCCC(CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-hexan-1-ol according to the GPA affording 24 mg (61%) of a purple powder. Rt=4.5 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15](O)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH:11]=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:23]1([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[CH:13]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccccc1C(O)(Cc1ccnc(NC(=O)OC(C)(C)C)c1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccccc1C(=Cc1ccnc(N)c1)c1ccccc1
Reaction time: 16 h
Yield: 98.5 %

Procedure:
[4-(2-Hydroxy-2-phenyl-2-o-tolyl-ethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (361 mg, 0.89 mmol) is dissolved in DCM (4 mL) and trifluoroacetic acid (2.0 mL) is added. After the mixture is stirred for 16 hrs, EtOAc (55 mL) is added followed by the addition of saturated NaHCO3 aqueous solution (15 mL) and water (35 mL). The mixture is stirred for another 15 min and the aqueous layer is separated. The aqueous layer is then extracted with EtOAc (2×35 mL) and all the organic layers are combined and concentrated to give 251 mg of the crude product which is used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C1C=CC=CC=1>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([N:20]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(=O)CCC(=O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 39 %

Procedure:
A mixture of 1-(4-chlorophenyl)pentane-1,4-dione (5.0 g., 0.024 mol, as obtained in Step-1) and 4-chloroaniline (3.33 g, 0.026 mol) in benzene (5.0 ml) was refluxed either over molecular sieves or using a Dean Stark apparatus. After three hours, benzene was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with water (2×100 ml.) and brine (1×50 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent evaporated off. The solid so obtained was washed with hexane to give 2.83 g (39.45%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]([C:19]([O:21]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[N:2]1.C(N(C(C)C)CC)(C)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].O>CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:19]([N:46]2[CH2:45][CH2:44][N:43]([C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])[CH2:48][CH2:47]2)=[O:21])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2noc3ccccc23)CC1
Yield: 33.1 %

Procedure:
A solution of bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (3.00 g, 6.19 mmol), diisopropylethylamine (1.08 ml, 6.19 mmol) and 1-(tert-butoxycarbonyl)piperazine (2.30 g, 12.4 mmol) in dimethyl sulfoxide (20 ml) was stirred at 70° C. for 2 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane, which was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and then recrystallized from a mixed solvent of hexane and ethyl acetate to give 710 mg (33.2%) of the desired product.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[NH2:10][CH2:11][CH:12]([OH:17])[CH2:13][C:14]([OH:16])=O.C1OC1C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C[Si](C)(C)Cl.C(#N)C>[C:24]([O:26][CH2:27][CH2:28][N:10]1[CH2:11][CH:12]([OH:17])[CH2:13][C:14]1=[O:16])(=[O:25])[CH3:23]
Reactant: NCC(O)CC(=O)O
Reactant: CCOC(=O)CBr
Agent: CC1CO1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: CC(=O)OCCN1CC(O)CC1=O
Temperature: 25 °C

Procedure:
Twenty-eight ml. of hexamethyldisilazane and 3 drops of trimethylchlorosilane are added to 10 g. γ-amino-3-hydroxybutyric acid in 100 ml. anhydrous acetonitrile. The reaction mixture is heated under reflux in a current of nitrogen until a clear solution is obtained. The resulting mixture is cooled to ambient temperature and 50 ml. propylene oxide are added thereto, followed by the dropwise addition of 9.4 ml. ethyl bromoacetate. The reaction mixture is heated under reflux for 15 hours, cooled to ambient temperature and then evaporated to dryness in vacuo. The residue obtained, which contains crude 2-(4-trimethyl-silyloxypyrrolidin-2-on-1-yl)-ethyl acetate is separated by chromatography on a eluting silica gel column, using ethyl acetate as elution agent. Eight g. 2-(4-Hydroxypyrrolidin-2-on-1-yl)-ethyl acetate are obtained in the form of a colorless oil; b.p. 180° C./0.8 mm.Hg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.COB(OC)OC.Cl.Br[C:26]1[CH:27]=[CH:28][C:29]2[O:35][CH2:34][CH2:33][C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][C:30]=2[CH:41]=1.B([O-])([O-])OC1C=CC(C(C)(C)C)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.C1(C)C(CCO)=CC=CC=1.O.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:26]2[CH:27]=[CH:28][C:29]3[O:35][CH2:34][CH2:33][C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][C:30]=3[CH:41]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: CC(C)(C)c1ccc(OB([O-])[O-])cc1
Agent: COB(OC)OC
Agent: Cc1ccccc1CCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1=Cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2OCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Under argon atmosphere, to a solution of 4-tert-butylbromobenzene (10.0 g) in diethylether (50 ml) was added n-butyllithium (1.6M, hexane solution) (32.3 ml) at −78° C., and the mixture was stirred for 1 hour. To the reaction mixture was dropwise added trimethyl boric acid (16 ml) in diethylether (30 ml), and the mixture was warmed to room temperature and stirred at room temperature 16 hours. To the reaction mixture were added 1N hydrochloric acid (50 ml) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:9) to give crude 4-tert-phenyl borate (0.84 g) as pale yellow oil. Under argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (500 mg), the above crude 4-tert-butylphenyl borate (0.59 g) and potassium carbonate (0.47 g) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphine palladium (0.06 g), and the mixture was refluxed for 20 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:19) to give ethyl 7-(4-tert-butyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (504 mg) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17](I)=[CH:18][C:19]=1[N:20]([C:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[O:14].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:18][C:19]=1[N:20]([C:28]([C@H:30]1[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]1)=[O:29])[CH:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1)=[O:14]
Reactant: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Temperature: 70 °C

Procedure:
To the mixture of 4-chlorophenylboronic acid (46.9 mg, 0.3 mmol) and 5-iodo-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (50 mg, 0.099 mmol), from step 5, in 5:1 mixture of toluene/MeOH (2.0 mL) was added a solution of Pd(PPh3)4 (12.0 mg, 0.01 mmol, 10 mol %) in toluene (1.0 mL) followed by aqueous 2M Na2CO3 solution (0.1 mL, 0.2 mmol). The resultant reaction mixture was heated at 70° C. for 16 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC (1 mm, 60 A°) using DCM/CHCl3/MeOH/Et3N (100:90:16:1) as an eluent furnished 5-(4-chloro-phenyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (35.0 mg, 71.5% yield). NMR 1H (CDCl3, 400 MHz): 7.53 (d, J=8.3, 2H), 7.4 (d, J=8.5, 2H), 7.0 (s, 1H), 4.67-4.58 (m, 1H), 3.84 (s, 3H), 2.82-2.64 (m, 1H), 2.2 (s, 3H), 2.14-1.35 (m), 0.763 (d, J=6.6, 3H), 0.76-0.56 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24].O>C1COCC1>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc12
Yield: 74.7 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 200 mg, 0.95 mmol) and 4-fluoro-3-(trifluoromethyl)aniline (510 mg, 2.85 mmol) in THF (4 mL) was stirred at rt for 2 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.47 (s, 1H), 8.83-8.80 (d, J=8.4 Hz, 1H), 8.72 (s, 1H), 8.42-8.39 (d, J=7.8 Hz, 1H), 8.31-8.25 (m, 2H), 7.86-7.81 (t, J=7.8 Hz, 1H), 7.64-7.58 (t, J=9.6 Hz, 1H).
Reaction SMILES: [P:1]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:2]CCCCCCCCCCCC.[C:41]([C:45]1[C:50]([OH:51])=[C:49]([CH3:52])[C:48]([CH2:53]Cl)=[C:47]([CH3:55])[CH:46]=1)([CH3:44])([CH3:43])[CH3:42]>>[C:41]([C:45]1[CH:46]=[C:47]([CH3:55])[C:48]([CH2:53][P:1](=[O:2])([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:49]([CH3:52])[C:50]=1[OH:51])([CH3:44])([CH3:43])[CH3:42]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: CCCCCCCCCCCCOP(OCCCCCCCCCCCC)OCCCCCCCCCCCC
Product: CCCCCCCCCCCCOP(=O)(Cc1c(C)cc(C(C)(C)C)c(O)c1C)OCCCCCCCCCCCC
Reaction time: 4 h

Procedure:
41 Grams of trilauryl phosphite and 16.1 grams of 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol were stirred together as a melt at 105° to 110° for 1 hour, followed by 110° to 120° for 2 hours, 120° to 125° for 10 hours and finally at 140° to 145° for 4 hours. The crude was topped in the "ASCO 50" Rotafilm Molecular Still at a wall temperature of 80° to 90° at 1 to 5 microns Hg. pressure to remove most of the by-product dodecyl chloride as well as small amounts of other volatiles. This topping procedure was repeated at a wall temperature of 200° to 210° at the same pressure to remove additional volatiles. The desired product distilled at a wall temperature of 250° to 260° at 1 micron Hg. pressure yielding the desired product as a colorless liquid which solidified to a white solid (m.p. 36° to 42°). (compound 3)
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.Cl[C:19]1[C:20]2[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1>>[CH2:9]([C:7]1[NH:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:19]3[C:20]4[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:3][C:4]=2[N:8]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Reactant: Nc1ccc2[nH]c(Cc3ccccc3)nc2c1
Product: Clc1cc2c(Nc3ccc4[nH]c(Cc5ccccc5)nc4c3)ncnc2cn1

Procedure:
Prepared according to Procedure A from 5-amino-2-benzyl-1H-benzimidazole and 4,6-dichloro-pyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 9.13(1H,s), 8.93(1H,s), 8.84(1H,s), 8.60(1H,s), 8.05(1H,dd), 7.88(2H,d), 7.50(6H, m), 4.61(2H,s); m/z (M+1)+387.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]2.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].C(OC(=O)C)C>C1COCC1>[C:23]1([O:22][C:20](=[O:21])[NH:1][C:2]2[C:11]3[CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc2c1C[C@H](O)CC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2c1C[C@H](O)CC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Next, a solution of (R)-8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol -(36.2 g) and pyridine (18.8 ml) in THF (850 ml) cooled at 0° C. was added phenyl chloroformate (28.8 ml). The mixture was stirred for 3 hours at room temperature, and then poured into ethylacetate. The mixture was washed with aqueous NH4Cl then with water, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. To the obtained residue was added acetonitrile, and the precipitates were collected and washed with a mixture of acetonitrile and diisopropyl ether (2:3) to obtain {(R)-7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl}carbamic acid phenyl ester (33.0 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26]([O:33][CH3:34])[CH:25]=1)=[N+]=[N-].O>C1COCC1>[CH3:34][O:33][C:26]1[CH:25]=[C:24]([CH2:23][NH2:20])[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=1
Reactant: COc1cc(CN=[N+]=[N-])cc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CN)cc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 67 %

Procedure:
PPh3 (0.0707 g, 0.27 mmol, 1.1 eq) was added to a stirred solution of 1-(azidomethyl)-3-methoxy-5-nitrobenzene (synthesis described herein) in 5 ml THF. After 5 min 1 ml of water was added, and the reaction was stirred overnight. The solvent was removed in vacuo. The residue was dissolved in EtOAc and extracted with 1N HCl (×1). The aqueous layer was adjusted to pH>8 with 1N NaOH and extracted with EtOAc (×1). This organic fraction was washed with brine (×1) and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo to yield 0.030 g (0.16 mmol, 67% yield) of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:23]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=3)=[N:6][CH:7]=2)[CH:34]=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)cc1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Product: CCCCCCCCOc1ccc(-c2ncc(-c3cccc(OCc4ccccc4)c3)cn2)cc1

Procedure:
5-Bromo-2-(4-octyloxyphenyl)pyrimidine and 3-benzyloxybenzeneboronic acid are reacted analogously to Example 1 to give 5-(3-benzyloxyphenyl)-2-(4-octyloxyphenyl)pyrimidine. ##STR35## Removal of the benzyl protecting group from 5-(3-benzyloxyphenyl)-2-(4-octyloxyphenyl) pyrimidine by hydrogenation analogously to Example i gives 5-(3-hydroxyphenyl)-2-(4-octyloxyphenyl) pyrimidine. ##STR36##
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN1C(=O)CCC1>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:3][C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[CH:9][NH:10]3)=[CH:6][CH:5]=2)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3cc[nH]c3c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaH (1.1 equivalents) is added to a solution of 6-hydroxyindole (1.0 equivalent) in NMP. The resulting mixture is stirred for 2 hours at room temperature. 2-Chloro-5-nitropyridine (1.1 equivalents) is added and the solution is heated to 100° C. for 2 hours. The solution is cooled and poured into water. The aqueous layer is extracted with EtOAc three times. The organic layers are combined and concentrated to yield the titled compound.