Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[N:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]2=[CH:13][C:12]=1[C:20](O)=[O:21].[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26][O:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:20]([C:12]2[CH:13]=[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]3[C:11]=2[NH:10][C:3]2[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:26][O:25]1
Reactant: CSc1ccc(Nc2c(C(=O)O)cc3ccncn23)c(F)c1
Reactant: CC1(C)OC[C@H](CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)cc3ccncn23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
7-(2-Fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (287 mg, 0.90 mmol), O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (133 mg, 0.90 mmol), HOBt (135 mg, 0.99 mmol), EDCI hydrochloride (191 mg, 0.99 mmol) and DIPEA (169 μL, 0.99 mmol) were dissolved in DMF (5 mL). The reaction was stirred at room temperature for 1 hour then 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 fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 30-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (246 mg, 61%). LCMS (Method B): RT=3.28 min, M+H+=447.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[I:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1>>[I:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1
Reactant: Ic1cccc(I)c1
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)c1cccc(I)c1

Procedure:
1-Iodo-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1,3-diiodobenzene as the dihalo compound of formula (III).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)[N:3]=1.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=1>O1CCOCC1>[F:24][C:16]([F:25])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:4]1[N:3]=[C:2]([NH:32][C:29]2[CH:28]=[C:27]([CH3:26])[NH:31][N:30]=2)[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COC(=O)c1cccc2c(Br)nc(C(F)(F)c3ccc(F)cn3)nc12
Reactant: Cc1cc(N)n[nH]1
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline-8-carboxylate (27 g, 65.5 mmol) in dioxane (300 mL) was added 5-methyl-1H-pyrazol-3-amine (12.7 g, 131 mmol) and the mixture was stirred at 50° C. overnight. The mixture was concentrated and the residue was triturated with water (1 L). The solid was collected by filtration, washed with water, and dried in air to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazoline-8-carboxylate as a solid. (26.7 g, 95%). LC-MS (ESI) m/z 429.6 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 12.23 (1H, s), 10.86 (1H, s), 8.82 (1H, d, J=8.2 Hz), 8.67 (1H, d, J=2.6 Hz), 7.99 (3H, m), 7.68 (1H, t, J=8.0 Hz), 6.05 (1H, s), 3.83 (3H, s), 2.19 (3H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[C:8]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][N:37]=[C:36](S(C)(=O)=O)[N:35]=3)[C:9]=2[CH:10]=[C:11]2[C:24]=1[N:23]1[CH2:25][C@@H:26]([CH3:30])[O:27][C@@H:28]([CH3:29])[C@@H:22]1[C:13]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]1=[O:21])[CH2:12]2.CS(C)=O.O(C(N)C)C>C1COCC1>[F:6][C:7]1[C:8]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:35]=3)[C:9]=2[CH:10]=[C:11]2[C:24]=1[N:23]1[CH2:25][C@@H:26]([CH3:30])[O:27][C@@H:28]([CH3:29])[C@@H:22]1[C:13]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]1=[O:21])[CH2:12]2
Reactant: COCCN
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: COC(C)N
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COCCNc1nccc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
2-Methoxyethanamine (8.70 μL, 0.10 mmol) was added o a solution of (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169, 50 mg, 0.09 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 3 hours, DMSO (1 ml) was added followed by the addition of 2 more equivalence of methoxylethanamine, the mixture was stirred at room temperature for over night. The crude was concentrated and purified by reverse phase silica gel column chromatography (20-70% MeCN in water gradient, 0.1% TFA) to give 37 mg of product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9](Cl)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([C:10]([F:13])([F:12])[F:11])=[N:17][N:16]=[N:15]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(N=C(Cl)C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nnnc2C(F)(F)F)cc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Five grams (22.6 mmol) of N-(4-methylphenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 3, 2.68 g (40.7 mmol) of sodium azide, 1.57 g (11.3 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 23 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×3). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 5.01 g of 1-(4-methylphenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 97.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[K+].[CH2:11](Br)[CH2:12][OH:13].N1C=CC=NC=1>C(O)C>[OH:13][CH2:12][CH2:11][N:4]1[CH:3]=[C:2]([F:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: O=c1ncc(F)c[nH]1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: c1cncnc1
Solvent: CCO
Product: O=c1ncc(F)cn1CCO
Yield: 50 %

Procedure:
5-Fluoropyrimid-2-one (0.008 mol) was dissolved in a solution of potassium hydroxide (0.008 mol) in absolute ethanol (100 ml) at 80° C. and ethylene bromohydrin (0.008 mol) added gradually with stirring. The alkylation was incomplete when the pH had become neutral. The reaction was further monitored by chromatography and equivalent amounts of potassium hydroxide and ethylene bromohydrin added until all the pyrimidine had been alkylated. The reaction mixture was then filtered and the filtrate evaporated to dryness before the residue was triturated with ether and extracted with warm acetone. Evaporation of the acetone solution left the title compound in 50% yield, m.p. 134°-136° C. after recrystallisation from ethanol; Found: C, 45.83; H, 4.42; Calc. for C6H7FN2O2 : C, 45.58; H, 4.46.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([F:10])[CH:3]=1.S(Cl)([Cl:13])=O>O1CCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:13])=[C:4]([F:10])[CH:3]=1
Reactant: OCc1ccc(Cl)cc1F
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Fc1cc(Cl)ccc1CCl

Procedure:
Then, 16.5 g of 4-chloro-2-fluorobenzylalcohol was dissolved in 150 ml of tetrahydrofuran and 1 ml of pyridine, to which 10 ml of thionyl chloride was added dropwise at 5° C., and the mixture was stirred for 2⅚ hours. After completion of the reaction, the reaction mixture was concentrated, and the precipitated crystals were collected by filtration. The filtrate was subjected to silica gel column chromatography, which afforded 18.5 g of 4-chloro-2-fluorobenzyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][C:16]([Cl:24])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(CCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: Cc1c(CCC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
830 mg of 3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-propionic acid and 4.2 ml of thionyl chloride were refluxed for 3 hours and then excess thionyl chloride was distilled off and the last traces were removed by entrainment with benzene to obtain 876 mg of 3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-propionyl chloride which was used as is for the next step.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:11])[C:5]([CH3:10])([CH:7]([CH3:9])[CH3:8])[N:6]=1.CN(C=O)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[Na]>C1COCC1>[C:2]([NH:6][C:5]([CH3:10])([CH:7]([CH3:9])[CH3:8])[C:4]([NH:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:24])=[O:25])=[O:11])(=[O:3])[CH3:1]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC1=NC(C)(C(C)C)C(=O)O1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2,4-Dimethyl-4-isopropyl-2-oxazolin-5-one (2.0 g) is mixed with DMF (50 mL), THF (70 mL) and sodium p-toluene sulfonamide (5.0 g), and the resulting mixture is heated at reflux for 16 hours. At the end of this time the mixture is cooled, and the solvents are removed under vacuum. The residue is mixed with water and the pH adjusted to 8 with NaHCO3. The aqueous mixture is extracted with ethyl acetate and the organic layers are discarded. The aqueous mixture is acidified to pH-4 with HCl and saturated with NaCl and extracted with ethyl acetate. The organic extracts are combined, dried over MgSO4, filtered and evaporated to give 0.66 of the title product.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][NH2:16])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:20])[CH:3]=1.CCN(CC)CC.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][NH:16][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:20])[CH:3]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 155.3 %

Procedure:
To a mixture of 2-(2-(4,5-dichloro-2-iodophenoxy)pyridin-4-yloxy)ethanamine (30 mg, 0.07 mmol), Et3N (35.7 mg, 0.35 mmol) in DCM (5 mL), 2-chloroethanesulfonyl chloride (11.5 mg, 0.07 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. Then solvent was removed under reduced pressure. The residue was taken in THF (2 mL) and H2O (2 mL), then K2CO3 (100 mg) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was partitioned between DCM and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/ethyl acetate=5:1) to afford the desired product (56 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ: 7.98 (d, J=5.6 Hz, 1H), 7.92 (s, 1H), 7.25 (s, 1H), 6.61-6.57 (m, 2H), 6.47 (d, J=2.0 Hz, 1H), 6.32 (d, J=16.4 Hz, 1H), 6.00 (d, J=10.0 Hz, 1H), 4.77 (t, J=5.2 Hz, 1H), 4.18 (t, J=5.2 Hz, 2H), 3.51-3.47 (m, 2H). ESI-MS m/z: 515.0[M+H]+.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C@H:5]([OH:17])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1>C1COCC1.O>[O:17]1[CH2:4][C@H:5]1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1
Reactant: CS(=O)(=O)N1CCN(C[C@@H](O)CCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CCN(C[C@@H]2CO2)CC1
Reaction time: 0.58 h

Procedure:
Sodium hydroxide (1.07 g, 26.7 mmol) was added to a vigorously stirred solution of 1-chloro-(R)-2-hydroxy-3-(4-methanesulfonylpiperazin-1-yl)propane, the product of the previous step (5.69 g, 22.2 mmol) in THF/water (150 mL/35 mL). The reaction mixture was stirred for 35 min, concentrated in vacuo to approximately 50 mL volume, diluted with chloroform (200 mL), and washed with 1M NaOH (2×70 mL) and brine (70 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to yield a white crystalline solid which was then recrystallised from hot EtOAc/hexane 1:1 (800 mL) to yield the title intermediate (2.62 g) as a white crystalline solid. (The filtrate could be further recrystallised to obtain additional product material.) ESMS (C8H16N2O3S): calcd. 221.10; found 221.3 (m/z): [M+H]+; 1H NMR (DMSO-d6): δ (ppm) 2.22 (dd, 1H), 2.45-2.60 (m, 5H), 2.69-2.75 (m, 2H), 2.87 (s, 3H), 3.02 (m, 1H), 3.11 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCCCBr
Yield: 100 %

Procedure:
A mixture of 6.0 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 29 ml of 1,5-dibromopentane and 2.2 g of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux. Additional portions (2.2 g) of potassium carbonate were added at 5, 21, 29 and 38 hours. Reflux was maintained for a total of 69 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a yellow oil which was purified by chromatography on 100 g of silica gel. Elution with 25% ethyl acetate-hexane gave 9.2 g (100%) of [4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(Cl)=[S:12]>Cl>[N:1]([C:2]1[C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[C:11]=[S:12]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc2ccoc12
Agent: Cl
Product: S=C=Nc1cccc2ccoc12

Procedure:
7-Amino-benzo[b]furan is reacted with thiophosgene in 3 N hydrochloric acid at room temperature over 1 hour to give 7-isothiocyanatobenzo[b]furan. (M. Pt. 45°-46° from petroleum ether.) Reaction of this isothiocyanate with ethanolamine in ether gives N-benzo[b]furan-7-yl-N'-2-hydroxyethylthiourea (m.pt. 138°-139° from methanol) which is used further in the crude state.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:23](O)(=[O:26])[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:23](=[O:26])[CH2:24][CH3:25])[CH2:10][CH2:9]1
Reactant: O=C(Nc1ccc(N2CCNCC2)c(Cl)c1)c1ccccn1
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCN(c2ccc(NC(=O)c3ccccn3)cc2Cl)CC1
Yield: 73.7 %

Procedure:
According to Scheme 5 Step 5 Method A: A solution of N-(3-chloro-4-(piperazin-1-yl)phenyl)picolinamide (0.19 mmol, 60 mg), propionic acid (0.19 mmol, 14 μL), EDCI.HCl (0.28 mmol, 54 mg), Et3N (0.38 mmol, 53 μL) and of hydroxybenzotriazole (0.21 mmol, 32 mg) in DCM (5 mL) was stirred at room temperature for 1 day. The solution was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure. The solid was triturated with water and finally with iPr2O to afford N-(3-chloro-4-(4-propionylpiperazin-1-yl)phenyl)picolinamide (0.14 mmol, 51 mg, 72%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH:16]([OH:18])[OH:17].C([Li])CCC.B(OC(C)C)(OC(C)C)OC(C)C.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([B:16]([OH:18])[OH:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OBO
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The 3-benzyloxybromobenzene of formula IV is converted to the boronic acid derivative by dissolving in THF and adding one equivalent of n-butyllithium at -78° C. After stirring at -78° C. for approximately 30 minutes, one equivalent of triisopropyl borate is added and the reaction is slowly warmed to room temperature, followed by acidification with aqueous hydrochloric acid to give a 3-benzyloxybenzene boronic acid compound of formula V. ##STR7##
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[SH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>C(O)C>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][S:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C(O)c1cccc(S)c1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1cccc(SCC(=O)c2ccccc2)c1
Yield: 120.3 %

Procedure:
To bromoacetophenone (250 mg, 1.16 mmole) and anhydrous K2CO3 (694 mg, 5.02 mmole) in ethanol, 193.6 mg (1.25 mmole) 3-mercaptobenzoic acid was added and the mixture refluxed overnight. The solvent was evaporated and water added to the solid residue. The basic aqueous solution was extracted with ethyl acetate to remove unreacted bromoacetophenone. The aqueous layer was acidified and extracted with ethyl acetate, dried, evaporated and the residue purified by flash chromatography using chloroform:methanol 95:5. Evaporation of the fractions resulted in a yellow powder (380 mg). M.S. m/s 271 (M−1)+. 1H NMR (DMSO) δ4.75 (2H, s, —CH2-), 7.39-7.7 (4H, m, 4×ArH), 7.75 (1H, d, ArH, J==5.61 Hz), 7.86 (1H, s, ArH), 8.02 (3H, d, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].C(OCC)(=O)C.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=[S:19])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(c2cccc(Br)c2)(C(F)F)N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: FC(F)C1(c2cccc(Br)c2)COCC(=S)N1

Procedure:
5-(3-Bromo-phenyl)-5-difluoromethyl-morpholin-3-one (6.10 g, 19.93 mmol) was dissolved in 63 ml dry pyridine, and P2S5 (5.32 g, 23.91 mmol) was added. The mixture was heated to 80° V for 2 hrs. After completion, the mixture was put between ethyl acetate and 1H HCl solution. Phases were separated and the organic phase was washed with 1 N HCl, saturated NaHCO3 solution and brine. The organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as off-white solid. 1H-NMR (360 MHz, DMSO-d6): 8.60 (s, 1H, NH), 7.80-7.35 (m, 4H), 6.54 (t, 1H, CHF2), 4.45 (m, 2H), 4.28 (d, 1H), 4.12 (d, 1H); MS: 322 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccnc(Cl)c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromobenzenesulfonyl chloride (3.19 g, 12.5 mmol) was added to a solution of 4-amino-2-chloropyridine (642 mg, 5 mmol) in pyridine (5 ml) and dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue suspended in 2M NaOH (25 ml) and heated at 60° C. for 1 h. The reaction mixture was extracted with ethyl acetate (2×25 ml). The extracts were washed, dried and evaporated. The residue was suspended in methanol and filtered. Evaporation of the filtrate and trituration with diethyl ether afforded the title compound (D3), 1H NMR (DMSO) δ: 6.54 (1H, d), 6.62 (1H, s), 7.60-7.63 (4H, m), 7.66 (1H, d).
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[C:17](Br)=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:7]=[C:6]([Br:28])[C:5]=1[OH:29].[K].[CH3:31]N(C=O)C>O>[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:7]=[C:6]([Br:28])[C:5]=1[O:29][CH3:31]
Reactant: CN(C)C=O
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: [K]
Solvent: O
Solvent: CI
Product: COc1c(Br)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1Br
Reaction time: 3 h
Yield: 91 %

Procedure:
Iodomethane (0.383 mL, 6.16.mmol) was added to a stirred suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (2.13 g, 4.4 mmol), potassium carbobnate (0.669 g, 4.34 mmol) and DMF (15 mL) at room temperature under a dry nitrogen atmosphere. After 3 h, the reaction mixture was diluted with water and the resulting solid was filtered and washed with water. The solid was taken up in dichloromethane and silica gel (40 mL) was added. The solvent was removed and the adsorbate was flash chromatographed (90:10 petroleum ether:dichloromethane) to provide the title compound as a white solid (2.0 g, 91%): mp 238.5-239.5° C.: NMR (CDCl3); δ 8.36 (ddd, J=8, 1, 1 Hz, 1H), 7.84 (ddd, J=8, 1, 1 Hz, 1H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.60 (s, 2H), 7.58 (ddd, J=8, 1, 1 Hz, 1H), 7.50 (ddd, J=8, 7, 1 Hz, 1H), 7.45 (ddd, J=8, 7, 1 Hz, 1H), 7.20 (ddd, J=8, 7, 1 Hz, 1H), 6.80 (ddd, J=8, 1, 1 Hz, 1H), 4.11 (s, 3H, CH3); MS (EI): [M+], 3 bromine isotope pattern, 574 (35%), 576 (95%) 578 (100%) 580 (45%); Anal. Calc. for C23H13Br3OS: C, 47.87, H, 2.27, N, 0.00. Found: C, 47.73, H, 1.88, N, 0.03.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=[C:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:17][C:18]2([C:19](=[O:20])[O:21][CH2:22][CH2:23]2)[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCCC12CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A stirred solution of N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (D8, 160 g of 75% purity, assume 0.51 mole) and α-methylene-γ-butyrolactone (D10, 50 g, 0.51 mole) in dichloromethane (1 liter) under nitrogen was cooled to 0° C. and then treated with a 1 M solution of trifluoroacetic acid in dichloromethane (50 ml, 0.05 mole), keeping the temperature below 5° C. The reaction mixture was allowed to warm to room temperature over 2 h, then washed with saturated sodium bicarbonate solution. The aqueous wash was extracted with dichloromethane and the organic solutions then combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to leave a pale yellow oil. This was distilled in vacuo to give the title compound (D11) as a colourless oil (96 g, 81%) b.p. 160°-170° C. at 1 mmHg.