Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=O.P(Cl)(Cl)([Cl:21])=O>>[Br:1][C:2]1[C:3]2[C:4](=[C:5]([Cl:21])[C:17]3[C:12]([N:11]=2)=[C:13]([Br:18])[CH:14]=[CH:15][CH:16]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cccc(Br)c1Nc1ccccc1Br
Product: Clc1c2cccc(Br)c2nc2c(Br)cccc12
Yield: 74 %

Procedure:
A suspension of 7.43 g (20.0 mmol) of 3-bromo-2-(2-bromophenylamino)benzoic acid (XXII) in 19.5 ml (213 mmol) of distilled phosphoryl chloride was heated to reflux for 2.5 h. Subsequently, the excess phosphoryl chloride was distilled off at room temperature under vacuum. The resulting brown oil was dissolved in chloroform, and the solution was added dropwise to ice-cooled diluted aqueous ammonia with stirring. After the mixture had reached room temperature, the phases were separated. The aqueous phase was extracted twice with chloroform, and the combined organic phases were dried over sodium sulfate. The solvent was distilled off under vacuum, and the residue was dried under high vacuum. Fractional sublimation of 7.00 g of raw product under high vacuum yielded 5.5 g (74% of theory) of 4,5-dibromo-9-chloroacridine (XXIII) as an analytically pure yellow solid with a melting point of 195-196° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=O.N1C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[C:14]([C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([C:2]#[N:1])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cc(C(N)=O)cc(C(C)(C)C)c1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)c1cc(C#N)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of give methyl 3-(aminocarbonyl)-5-tert-butylbenzoate (11.8 g, 0.0451 mol) in THF (88) was added pyridine (5.5 mL, 0.068 mol) and TFAA (9.6 mL, 0.068 mol). The reaction mixture was allowed to stir at rt for 3 h and then quenched by the addition of aq sat NaHCO3 and brine. The mixture was extracted with EtOAc. The organic solutions were combined and washed with sodium bicarbonate, brine, 1M HCl, water and brine. The solution was dried over MgSO4, filtered, and concentrated to give methyl 3tert-butyl-5-cyanobenzoate (9.5 g, 70% pure, 68%). 1H NMR (400 MHz, d6-DMSO) δ: 8.77 (s, 1H), 8.48 (s, 1H), 8.19 (m, 1H), 8.17 (m, 1H), 8.15 (1, m), 3.88 (s, 3H), and 1.31 (s, 9H). LCMS: ES+ 218.2
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][NH:20][CH2:21][C:5]=3[C:4]=2[CH:3]=1.[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH2:23].C(O)(=O)C>CO>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:6]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:22][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: Fc1ccc(-n2c3c(c4cc(F)ccc42)CNCC3)cc1
Reactant: C=Cc1ccccn1
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(-n2c3c(c4cc(F)ccc42)CN(CCc2ccccn2)CC3)cc1
Yield: 89.9 %

Procedure:
A mixture of 8-fluoro-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3 g, 0.01 mole), 2-vinylpyridine (1.7 g, 0.01 mol) and 2 mL of glacial acetic acid were refluxed for 48 hours in 30 mL of methanol. The solvent was removed in vacuo and the separated solid was purified by HPLC using ethyl acetate as the eluant to afford 3.5 g (89.9% yield) of the title compound. It was converted to the dihydrochloride salt; mp. 267°-270° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([F:15])[C:3]=1[NH:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH:21]=[CH:20][C:19]=1[F:31].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([F:15])[C:3]=1[NH:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH:21]=[CH:20][C:19]=1[F:31]
Reactant: CCOC(=O)COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A solution of ethyl 2-[4-chloro-2-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (80 mg, 0.18 mmol, 1.0 eq) in THF (6 mL) was added to a 1M solution of NaOH (2 mL, 2 mmol, 11.1 eq). The reaction mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo and the aqueous solution diluted with water. The solution was adjusted to pH 3 by addition of diluted HCl and the precipitate that formed collected by filtration, washed with water and dried in vacuo to give the title compound (I(k)) as white solid (65 mg, 87%).
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[N:17]([CH2:23][CH2:24]N(C)C)[N:16]=[CH:15]3)=[CH:6][CH:5]=1.[Br:28]C1C=C2C(=CC=1)C(=O)N(CC[CH2:42][N:43]([CH3:45])[CH3:44])N=C2.BrC1C=C2C(=CC=1)C(=O)N(CCN(C)C)N=C2>>[BrH:28].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[N:17]([CH2:23][CH2:24][CH2:42][N:43]([CH3:45])[CH3:44])[N:16]=[CH:15]3)=[CH:6][CH:5]=1
Reactant: COc1ccc(/C=C/c2ccc3c(=O)n(CCN(C)C)ncc3c2)cc1
Reactant: CN(C)CCCn1ncc2cc(Br)ccc2c1=O
Agent: Br
Agent: CN(C)CCn1ncc2cc(Br)ccc2c1=O
Product: COc1ccc(/C=C/c2ccc3c(=O)n(CCCN(C)C)ncc3c2)cc1

Procedure:
The procedure used was identical to that used in preparing 6-[2-(4-methoxyphenyl)ethenyl]-2-[2-(dimethylamino)ethyl]phthalazin-1(2H)-one (Example III above), except that 6-Bromo-2-[3-(dimethylamino)propyl]phthalazin-1(2H)-one was substituted for 6-Bromo-2-[2-(dimethyamino)ethyl]phthalazin-1(2H)-one. The weight of product obtained from 102 gm starting halide was 104 gm after recrystallization from 50 ml of methoxyethanol. It melted at 232°-234° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>C1COCC1>[CH2:3]([O:10][C:14]1[CH:15]=[CH:16][N:17]=[C:12]([Cl:11])[N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nccc(OCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a cooled (1-2° C.) suspension of sodium hydride (60% in mineral oil) (1.5 equiv) in 250 ml THF, benzyl alcohol (1.0 equiv.) was added dropwise and the mixture stirred 30 min under N2. This suspension was then added in small portions (via syringe, over 1 hr) to a solution of 2,4-dichloropyrimidine (1.5 equiv.) in THF also at 1-2° C. (internal thermometer). The resulting mixture (0.06 M) was stirred at temp <2° C. for 2.5 hrs, then quenched with NH4Cl(sat.) and extracted with EtOAc. Upon separation, the organic layer was washed with NaCl(sat.), dried over Na2SO4, concentrated and purified by silica gel chromatography (hexanes/DCM eluant) to yield 4-(benzyloxy)-2-chloropyrimidine (24%). LC/MS=221.0 (M+H), LC=3.93 min.
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[O:18]=[C:19]1[C@@H:22]([NH:23]C(OCC2C=CC=CC=2)=O)[CH2:21][N:20]1[S:34]([O-:37])(=[O:36])=[O:35]>CN(C)C=O.[Pd]>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[NH2:23][C@H:22]1[CH2:21][N:20]([S:34]([O-:37])(=[O:36])=[O:35])[C:19]1=[O:18]
Reactant: O=C(N[C@H]1CN(S(=O)(=O)[O-])C1=O)OCc1ccccc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: N[C@H]1CN(S(=O)(=O)[O-])C1=O

Procedure:
(S)-2-Oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, tetrabutylammonium salt (2 g; see Example 4) is dissolved in 100 ml of dimethylformamide and hydrogenated for about 30 minutes with 1 g of palladium on charcoal (10%) as catalyst. The catalyst is filtered off and the dimethylformamide is removed leaving the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)[S:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[CH3:19][N:20](C=O)C>ClCCl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:16]1([CH2:15][NH:14][C:10]2[S:11][C:12]([CH3:13])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:19]#[N:20])=[CH:3][CH:4]=3)[N:9]=2)[CH2:18][CH2:17]1
Reactant: Cc1sc(NCC2CC2)nc1-c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Product: Cc1sc(NCC2CC2)nc1-c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Slurry 1-bromo-4-(2-cyclopropylmethylamino-5-methyl-thiazol-4-yl)-benzene (1.0 g, 3.09 mmol), 1,1′-bis-(diphenylphosphino)ferrocene (275 mg, 0.494 mmol), zinc cyanide (325 mg, 2.75 mmol) and tris(dibenzylideneacetone)dipalladium(0) (254 mg, 0.28 mmol) in DMF (6 mL) and heat in a sealed tube at 110° C. overnight. Cool the mixture to room temperature, dilute with dichloromethane (100 mL) and filter over Celite®. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel (40 g) eluting with hexane/EtOAc (19:1 to 7:3 gradient over 30 min; 40 mL/min) to obtain the desired intermediate (416 mg, 52%) as a yellow solid. MS (ES+) m/z: 270 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[C:4]([F:21])[CH:3]=1.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:18]([C:17]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:21])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)=[O:20])=[CH2:23]
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of 4-(4-bromo-2-fluorophenylamino)-1H-indazole-5-carboxylic acid (115 mg, 0.33 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (51 mg, 0.49 mmol) in DMF (3 mL) was added EDCI (69 mg, 0.36 mmol), HOBt (49 mg, 0.36 mmol) and DIPEA (61 μL, 0.36 mmol). The reaction mixture was stirred at room temperature for 4 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (96 mg, 67%). LCMS (Method B): RT=3.43 min, [M−H]−=433/435.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:40][CH2:41][CH3:42])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[C:22]([O:40][CH2:41][CH3:42])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: CCOc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OCC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (265 mg) and 4-(4-chloromethyl-2-ethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (447 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (548 mg, yield: 82%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:19]=[C:18]([C:32]#[N:33])[N:17]=2)[CH2:12][CH2:11]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[C:6]([CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[N:19]=[C:18]([C:32]#[N:33])[N:17]=2)[CH2:14][CH2:15]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CCN1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCN(CCC(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of the compound of Example 4 (22 mg) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml). The resulting solution was stirred at room temperature for 1 hr before concentrating in vacuo. The residue was then purified using preparative HPLC to give 4-[4-(2-carboxy-ethyl)-piperazin-1-yl]-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt as a white solid (8.5 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Br[C:14]1[S:18][N:17]=[CH:16][C:15]=1[N+:19]([O-:21])=[O:20].C([O-])(O)=O.[Na+].O>O1CCOCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N+:19]([C:15]1[CH:16]=[N:17][S:18][C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=1)([O-:21])=[O:20]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cnsc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(-c2sncc2[N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 10000 %

Procedure:
To a solution of 4-carbamoylphenylboronic acid (3Q) (157 mg, 0.96 mmol) and 5-bromo-4-nitroisothiazole (P) (200 mg, 0.96 mmol) in dioxane was bubbled was nitrogen gas for 5 min Bis(tri-tert-butylphosphine)palladium (0) (49 mg, 0.096 mmol) and 1.2M NaHCO3 water solution (241 mg, 2.9 mmol) was added and stirred at 120° C. under nitrogen atmosphere for 15 min The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water, and concentrated in vacuo at room temperature (25° C.) to afford the product 4-(4-nitroisothiazol-5-yl)benzamide (3C4) (250 mg, 96 mmol)
Reaction SMILES: [C:1]([N:4]1[C:12](=O)[C:11]2[C:6](=[CH:7]C=CC=2)C1=O)(=[S:3])C.[N:15]1[CH:20]=[CH:19]C=[CH:17][C:16]=1[S:21]CCN>C(Cl)(Cl)Cl>[N:4]1[CH:12]=[CH:11][CH:6]=[CH:7][C:1]=1[S:3][CH2:19][CH2:20][NH:15][C:16](=[S:21])[CH3:17]
Reactant: CC(=S)N1C(=O)c2ccccc2C1=O
Reactant: NCCSc1ccccn1
Solvent: ClC(Cl)Cl
Product: CC(=S)NCCSc1ccccn1
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
To a mixture of 2-aminoethanethiol hydrochloride (4.07 g, 35.6 mmol) in dioxane (75 mL) at 50° C., add sodium hydride (60% in mineral oil, 2.84 g, 71.0 mmol) at room temperature under nitrogen. Allow the reaction to stir for 5 minutes and add 2-chloropyridine (3.5 mL, 37 mmol) to the mixture. Reflux the mixture for 24 hours and cool to room temperature. Add water (100 mL), and methylene chloride (300 mL) to this mixture. Extract the aqueous layer with methylene chloride (3×50 mL). Wash the combined organic phase with brine (200 mL), dry over magnesium sulfate, filter and concentrate to an orange oil. Flash chromatography on silica gel eluting with 50% (80:18:12 CHCl3/MeOH/concentrated NH4OH)/methylene chloride affords the title compound as a yellow oil (1.67 g, 30%). 1H NMR (CDCl3) δ 8.43 (m, 1H), 7.44 (m, 1H), 7.21 (m, 1H), 6.97 (m, 1H), 3.30 (m, 2H), 3.02 (m, 2H); MS (ES) m/z:═155 [C7H10N2S+H]+. Add 2-thioacetyl-isoindole-1,3-dione (0.7 g, 3.2 mmol) to a solution of 2-(pyridin-2-ylsulfanyl)ethylamine (0.5 g, 3.2 mmol) in CHCl3 (20 mL) at 0° C. After 15 minutes, concentrate and purify the residue by flash chromatography on silica gel eluting with 40% EtOAc/Hex containing 2% NH4OH to afford N-(2-(pyridin-2-ylsulfanyl)ethyl)thioacetamide (0.4 g, 58%) as a pale yellow oil. 1H NMR (CDCl3) δ 10.26 (br s, 1H), 8.41-8.43 (m, 1H), 7.57 (dt, J=7.35 Hz, J=1.8 Hz, 1H), 7.31 (dd, J=8.10 Hz, J=0.96 Hz, 1H), 7.09-7.13 (m, 1H), 3.87-3.92 (m, 2H), 3.40-3.43 (m, 2H), 2.53 (s, 3H); MS (APCI): m/z 213 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>S1(CCCC1)(=O)=O.O>[CH2:18]([O:1][C:2]1[CH:10]=[C:9]([O:11][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 32.3 %

Procedure:
2,4-Dihydroxybenzoic acid (48.0 g), anhydrous potassium carbonate (21.5 g), benzyl chloride (39.4 g) and dry sulpholane (400 ml) were heated together, with stirring, at 100° C. for 20 hours. The mixture was then poured into water (2 liters), the resulting oil was separated and the aqueous layer extracted with diethyl ether (300 ml). The ether extract was evaporated and its residue was combined with the said oil layer and washed with water (500 ml) to remove sulpholane, and then was washed with brine, the aqueous washings were extracted with diethyl ether (400 ml), and the combined oil and ether extract were dried and evaporated to give crude benzyl 2,4-dihydroxybenzoate (64 g), m.p. 83°-88° C. This ester (20 g) was treated with anhydrous potassium carbonate (17.0 g) and benzyl chloride (22.8 g) in dry sulpholane (300 ml) and the mixture was stirred and heated at 140° C. for 3 hours. It was allowed to cool and was then poured into water (1500 ml) and the mixture was neutralised to pH 7 by treatment with hydrochloric acid. The precipitated crude benzyl 2,4-dibenzyloxybenzoate was heated at reflux with a mixture of aqueous sodium hydroxide solution (2N; 400 ml) and ethanol (50 ml) for 10 hours. The solution was allowed to cool, and was then diluted with a large volume of water and acidified to pH 1 by treatment with hydrochloric acid (2N) to give a white solid which was filtered off and recrystallized from ethanol to give 2,4-dibenzyloxybenzoic acid (16.8 g), m.p. 126°-128° C.
Reaction SMILES: [N:1]1[C:6]([NH2:7])=[CH:5][C:4]([NH2:8])=[N:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[CH:2][N:1]=[C:6]([NH:7][C:9](=[O:11])[CH3:10])[CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(N)ncn1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(N)ncn1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a stirred suspension of pyrimidine-4,6-diamine (500 mg, 4.55 mmol) in dioxane (20 mL) was added acetic anhydride (465 mg, 4.55 mmol) and the resulting mixture was heated under reflux for 15 hours. The reaction was cooled to room temperature and the resulting precipitate was collected by filtration. The filtercake was dissolved in 1N HCl and the pH of the aqueous phase adjusted to 7 by the addition of 1N NaOH. The resulting white precipitate was collected by filtration and dried to afford the desired product as a white solid (420 mg, 61% yield). LCMS (ESI) m/z: 152.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[C:13]([CH3:25])[C:12]=2[C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:33]N1C(=O)CCC1=O>>[Br:33][CH2:25][C:13]1[C:12]([C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=1
Reactant: CCCCCC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Product: CCCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Reference Example 5, 4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxy-2-methylquinoline was brominated with N-bromo-succinimide (NBS) to give 2-bromomethyl-4-(3,4-dimethoxy-phenyl)-3-hexanoyl-6,7-dimethoxyquinoline- This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 146°-147° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([OH:39])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)[N:34]=1.[CH2:55](O)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)[N:34]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Reactant: CCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
2.00 g (11.5 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 3.00 g (11.5 mmol) of triphenylphosphine in 50 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 2.42 g (7.7 mmol) of 2-fluoro-3-hydroxy-6-(4-octyloxyphenyl)pyridine and 1.00 g (7.7 mmol) of 1-octanol are then added. After a reaction time of 18 hours at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 95:5 hexane/ethyl acetate). Recrystallization from acetonitrile gives 1.38 g of 2-fluoro-3-octyloxy-6-(4-octyloxyphenyl)pyridine. ##STR19##