Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([OH:24])[CH:5]([N:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.[H-].[Na+].F[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N+:35]([O-:37])=[O:36].Cl>CN(C)C=O>[CH:1]1([CH:4]([O:24][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[N+:35]([O-:37])=[O:36])[CH:5]([N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: O=C(O)C(C(O)C1CC1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(C(Oc1ccc(F)cc1[N+](=O)[O-])C1CC1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h

Procedure:
1.30 g (4.00 mmol) racemic (2R,3S and 2S,3R)-3-Cyclopropyl-2-dibenzylamino-3-hydroxy-propionic acid in 4 ml dimethylformamide were added at 0° C. to 0.37 g (8.48 mmol) sodium hydride (55%) in 4 ml dimethylformamide. The suspension was stirred for 2 hours and then 0.96 ml (8.8 mmol) 2,5-difluoro-nitrobenzene in 3.4 ml dimethylformamide were added. After stirring overnight the mixture was poured on ice/water. The pH was adjusted to 1 by adding aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with diethylether/heptane (25:75 to 100:0) yielded 1.57 g (85%) racemic (2R,3S and 2S,3R)-3-cyclopropyl-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-propionic acid as light yellow foam, MS m/e (%): 465.0 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[CH2:15]([Mg]Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>CCOCC>[NH2:1][C:2]1[NH:7][CH:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1
Reactant: CCCc1nc(C)c2cnc(N)nn12
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCc1nc(C)c2n1N=C(N)NC2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 4) (1.9 g.) was added to benzyl magnesium chloride (prepared from benzyl chloride (6.3 g.) and magnesium (1.2 g.)) in ether (400 ml.), and the mixture was stirred for 4 hours at room temperature. Aqueous ammonium chloride (50 ml., 20%) was added and the aqueous layer was separated and extracted with ethyl acetate. The extracts were dried over magnesium sulphate, filtered and evaporated and the residue was chromatographed on silica gel (100 g.). Fractions eluted with ethyl acetate were discarded. The fractions eluted with a mixture of ethyl acetate and methanol (4:1) were evaporated to give 2-amino-4-benzyl-3,4-dihydro-5-methyl-7-propylimidazo [5,1-f]-as-triazine as a gum (0.83 g.). This gum (0.7 g.) and acetyl chloride (0.3 ml.) in glacial acetic acid (10 ml.) were heated at 100° for 2.5 hours. Acetic acid was distilled off and the residue was crystallised from a mixture of ethanol and ethyl acetate to give a white solid, m.p. 240°-241°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]#[N:12])=[N:8][CH:9]=1)([O-])=O.Cl[Sn]Cl>Cl.C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]#[N:12])=[N:8][CH:9]=1
Reactant: N#CCc1ccc([N+](=O)[O-])cn1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: N#CCc1ccc(N)cn1
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a mixture of (5-nitro-pyridin-2-yl)-acetonitrile (500 mg, 3.06 mmol) in concentrated aqueous HCl (3.1 ml) and ethanol (3.1 ml) at 0° C. SnCl2 (2.3 g, 10.11 mmol) was added. The mixture was allowed to come to room temperature and was stirred for 2 h. The mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a brown oil (300 mg, 74%).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].C(C1C(N)=C(C)C([N+]([O-])=O)=CC=1)C.[Br:18][C:19]1[C:24]([CH3:25])=[C:23]([N+]([O-])=O)[CH:22]=[CH:21][C:20]=1[CH2:29][CH3:30]>O.Br>[Br:18][C:19]1[C:20]([CH2:29][CH3:30])=[C:21]([N+:1]([O-:3])=[O:2])[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: CCc1ccc([N+](=O)[O-])c(C)c1Br
Reactant: O=N[O-]
Agent: Br
Agent: CCc1ccc([N+](=O)[O-])c(C)c1N
Agent: [Na+]
Solvent: O
Product: CCc1c([N+](=O)[O-])ccc(C)c1Br
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
NaNO2 (7.7 g, 110 mmol) in 15 mL of water was added slowly to a stirred solution of the products of Step 1 (19 g, 106 mmol) in 48% aqueous HBr (35 mL) at 0° C. CuBr (1.4 g, 10 mmol) in 48% aqueous HBr (10 mL) was added dropwise. After stirring for 15 mins, the mixture was heated at 90° C. for 2 hrs. After cooling, the mixture was diluted with water and extracted 5 times with EtOAc. The combined organic phases were concentrated and purified by silica gel column chromatography (PE/EtOAc=50:1) to yield a mixture of 2-bromo-1-ethyl-3-methyl-4-nitro-benzene and 2-bromo-3-ethyl-1-methyl-4-nitro-benzene (23 g, yield 95%).
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([N+:11]([O-:13])=[O:12])=[C:5](Cl)[N:4]=1>C(O)(=O)C>[Br:1][C:5]1[N:4]=[C:3]([CH3:2])[NH:8][C:7](=[O:9])[C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: Br
Reactant: COc1nc(C)nc(Cl)c1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 25 °C
Reaction time: 44 h
Yield: 68.9 %

Procedure:
56.6 ml (503 mmol) of hydrobromic acid solution (48% in water) were added dropwise to a solution of 20.5 g (101 mmol) of the 2-methyl-4-methoxy-5-nitro-6-chloro-pyrimidine [Helv. (1958), 41, 1806] in 450 ml of acetic acid and the reaction mixture was stirred at room temperature for 44 hours. It was then evaporated under reduced pressure and the residue formed poured into 500 ml of an ice/water mixture and extracted 3 times with 500 ml of dichloromethane. The combined dichloromethane phases were washed with 100 ml of water and evaporated under reduced pressure. There were thus obtained 16.3 g (69.6 mmol, yield 69%) of the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one as light yellow solid, which was used without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][CH:16]5[C:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[CH:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)[CH:32]=1
Reactant: OB(O)c1cccnc1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4cccnc4)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 3-pyridylboronic acid by the method described for Example 36 Step 3. MS (ES+) 521 ([MH]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:4]=2[C:5](=[O:8])[N:6]([CH2:20][CH3:21])[N:7]=1
Reactant: Cc1ccc(-n2ccc3c(Cl)n[nH]c(=O)c32)c(C)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Cl)c2ccn(-c3ccc(C)cc3C)c2c1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
A mixture of 4-chloro-1-(2,4-dimethylphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (100 mg, 0.365 mmol), ethyl iodide (0.032 ml, 0.40 mmol), potassium carbonate (100 mg, 0.73 mmol) and DMF (1 ml) was stirred at room temperature for 7 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 102 mg (93%) of the title compound as crystals.
Reaction SMILES: Cl[C:2]1[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.O>O1CCCC1>[O:25]1[CH2:26][CH2:27][N:22]([C:2]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:12][C:3]=2[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5])[CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: O=C(OCC(F)(F)F)c1ccc(OCC(F)(F)F)nc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCC(F)(F)F)c1ccc(OCC(F)(F)F)nc1N1CCOCC1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 101.3 %

Procedure:
A mixture of 2,2,2-trifluoroethyl 2-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (0.30 g, 0.89 mmol, Step-1), morpholine (0.77 mL, 8.89 mmol) and triethylamine (0.62 mL, 4.44 mmol) in tetrahydrofuran (2 mL) is stirred at 140° C. for 10 minutes under microwave irradiation. The reaction mixture is poured into water and extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo to give 0.35 g (>99% yield) of the title compound as a yellow solid. This material is used for the next reaction (Step-3) without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:24]1([C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)O)[OH:25].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:23][C:31]3[CH:30]=[CH:29][CH:28]=[CH:26][C:24]=3[O:25]2)=[CH:20][CH:19]=1
Reactant: Oc1ccccc1O
Reactant: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 35.9 %

Procedure:
A solution of the above ketone (957 mg, 3.00 mmol), catechol (660 mg, 6.00 mmol) and p-TsOH.H2O (1.14 g, 6.00 mmol) in xylene (20 mL) was heated at reflux using a Dean-Stark apparatus to remove water for 24 hours. Standard work-up and purification gave 4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pale yellow oil (335 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:14][C:15]1[C:23]2[C:22]([NH2:24])=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[N:16]=1.C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O.CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:24][C:22]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:23]=3[C:15]([CH3:14])=[N:16][N:17]4[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(O)c1cnc2cc(F)ccn12
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
7-Fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (0.081 g, 0.449 mmol) was dissolved in thionyl chloride (2 mL). To this was added a few drops of DMF and the mixture stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure and the resulting solid was dissolved in 3 mL of 1:2 DCM:DMF. To this was added 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.114 g, 0.451 mmol) followed by diisopropylethylamine (235 μL, 1.35 mmol). This mixture was stirred at ambient temperature for 2 hours, then diluted with water (22 mL), forming a beige precipitate with stirring for several hours. The solids were collected to give 0.100 g (54%) of the title compound. MS (APCI), positive scan, m/z=415.2 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:13])=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[Cl:14]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1.[K+].[Br-]>C(#N)C.C(OCC)(=O)C>[Cl:14][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH2:13])=[C:5]([S:9]([NH2:12])(=[O:10])=[O:11])[CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1cccc(S(N)(=O)=O)c1N
Agent: O=C1CCC(=O)N1
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1cc(Cl)cc(S(N)(=O)=O)c1N

Procedure:
To a solution of 3-ethyl-2-aminobenzenesulfonamide (0.5043 g, 2.52 mmol) in 10 mL acetonitrile was added N-chlorosuccinimide (0.3163 g, 2.37 mmol). The mixture was stirred at reflux for 1 2.5 h, cooled, filtered, and concentrated in vacuo. Reaction was incomplete by 1H NMR; the purple solids were redissolved in acetonitrile and additional NCS (0.1019 g, 0.76 mmol) was added. The mixture was refluxed for 1 5 minutes and worked up as before. Column chromatography on the mixture of succinimide and D (40% ethyl acetate:hexanes) gave pure D (0.5224 g, 94%), m.p. 134-135° C. 1H NMR (300 MHz, DMSO): δ7.45 (3H, s), 7.19 (1H, d, J=2.1 Hz), 5.76 (2H, s), 2.53 (2H, q, J=7.3 Hz), 1.14 (3H, i, J=7.3 HZ). 13C NMR (300 MHz, DMSO): δ141.9, 131.8, 131.2, 125.4, 124.8, 118.1, 23.4, 12.7. FT-IR (KBr): 3457.8, 3427.9, 3358.4, 3268.9, 3080.1, 2970.8, 2364.5, 2334.7, 1630.6. 1556.1, 1541.2. 1451.7. 1312.6. 1188.3, 1148.6, 905.1, 875.3, 762.2, 611.3 cm-1. HRMS: M+ calculated=234.0230, found=234.0227.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[ClH:9].[CH3:10][O:11][NH2:12].CO.C(=O)([O-])[O-].[K+].[K+]>O>[ClH:9].[CH3:10][O:11][N:12]=[C:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(=O)CC1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CON=C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
1-Methyl-4-piperidone (5 g, 44.2 mmol) and methoxyamine hydrochloride (3.69 g, 44.2 mmol) were taken into 25 mL of methanol and stirred at room temperature for 2 days. The reaction mixture was evaporated in vacuo to afford a solid residue. The residue was dissolved in water, made basic with solid potassium carbonate, and extracted with dichloromethane (3×100 mL) . The combined extracts were dried over anhydrous sodium sulfate and evaporated to give a clear, yellow liquid that was purified on silica gel, eluting with dichloromethane-methanol (95:5) to afford 2.55 g of the desired product. Treatment with ethereal hydrogen chloride gave the hydrochloride salt, 2.99 g, m.p. 145°-147° C.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([O:21][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (648 mg, 1.93 mmol) (obtained as described in Reference Example 2(6)) in methylene chloride (20 ml) were added methanesulfonyl chloride (0.31 ml, 3.95 mmol) and triethylamine (0.55 ml, 3.95 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from a mixture of n-hexane and ethyl acetate to afford 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (789 mg, yield 99%) as a white solid.
Reaction SMILES: [Na].Br[CH2:3][CH:4]=[C:5]([CH3:18])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])=[C:13]([CH3:15])[CH3:14].[CH3:19][OH:20]>>[CH3:19][O:20][CH2:3][CH:4]=[C:5]([CH3:18])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])=[C:13]([CH3:15])[CH3:14]
Reactant: CO
Reactant: CC(=CCBr)CCC=C(C)CCC(C)=C(C)C
Agent: [Na]
Product: COCC=C(C)CCC=C(C)CCC(C)=C(C)C

Procedure:
To a solution containing 8.6 g. of sodium dissolved in 172 ml. of absolute methanol, then was added dropwise over a period of 30 minutes, 111 g. of 1-bromo-3,7,10,11-tetramethyl-2,6,10-dodecatriene. The reaction mixture was refluxed for 16 hours. After reflux, the reaction mixture was dried under vacuum and poured onto ice water. The resulting mixture was exhaustively extracted with petroleum ether (b.p. 40°-45°C.). The combined petroleum ether extracts were washed neutral with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on Kieselgel with hexane/diethylether (95:5 parts by volume) and distillation, there was obtained 1-methoxy-3,7,10,11-tetramethyl-2,6,10-dodecatriene, b.p. 87°-88°C./0.02 mmHg; nD20 = 1.4826
Reaction SMILES: [C:1]([N:9]1[CH:18](C(O)=O)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1(=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[CH:24]=[CH:23]1>C(OC(=O)C)(=O)C>[C:2]1([C:1]2[N:9]3[CH2:10][C:11]4[C:16]([CH2:17][C:18]3=[C:23]3[C:24]=2[C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:22]3=[O:33])=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: O=C(O)C1Cc2ccccc2CN1C(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccccc2C(=O)c2c1c1n(c2-c2ccccc2)Cc2ccccc2C1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
A mixture of 2-benzoyl-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid (6.0 g) and 1,4-naphthalenedione (6.75 g) in acetic anhydride (240 ml) was stirred at about 100° C. for 20 minutes. The reaction mixture was allowed to stand at room temperature for 48 hours, and the green solid (7.16 g) was collected by filtration. The crude product was recrystallised from chloroform-petroleum ether (b.b. 40°-60° C.) to give the title compound (5.04 g) m.p. 267° C. (decomp), λmax (in ethanol) 246.5 nm (ε45,500), 320 nm (ε2,440), 388 nm (ε6,120).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][CH:21]([F:39])[O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1>>[F:39][CH:21]([F:20])[O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: CC1(C)OB(c2ccc(F)cc2OC(F)F)OC1(C)C
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OC(F)F)n2)c1

Procedure:
Example 15 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and 2-[2-(difluoromethoxy)-4-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Focus Synthesis LLC). The batch was purified by preparative HPLC:
Reaction SMILES: C([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])(OC(C)(C)C)=O>CN(C)C=O>[NH2:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: CN(C)C=O
Product: NC(=O)CC[C@H](N)C(=O)O
Reaction time: 8 h

Procedure:
To the product of Step (D) above there is added with mixing 4 molar excess of the p-nitrophenyl ester of Boc-L-glutamine [Gln (ONp), Peninsula, supra.] dissolved in 15-20 ml. of dimethylformamide containing 1.5 M urea. The resulting mixture is shaken overnight, filtered, washed with dimethylformamide-ethanol mixture and dried.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][C@H:15]1[CH2:20][NH:19][C@H:18]([CH3:21])[CH2:17][NH:16]1.O>CN(C=O)C>[CH3:14][C@H:15]1[CH2:20][NH:19][C@H:18]([CH3:21])[CH2:17][N:16]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1
Temperature: 80 °C

Procedure:
A 1 g portion of 4-fluoro-2-trifluoromethylbenzonitrile and 2.4 g of trans-2,5-dimethylpiperazine were dissolved in 30 ml of DMF and heated at 80° C. for a whole day and night. The reaction solution was mixed with water, extracted with ethyl acetate and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography, and 1.3 g of the title compound was obtained from chloroform-methanol (10:1, v/v) eluate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3([CH3:20])[CH3:19])[N:8]2[CH3:11])=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1.[O:27]1[CH2:30][C:29](=O)[CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH:29]4[CH2:30][O:27][CH2:28]4)[CH2:15][C:14]3([CH3:20])[CH3:19])[N:8]2[CH3:11])=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: Cn1c(CN2CCNCC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CCN(C3COC3)CC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 16 h

Procedure:
A mixture of 2-chloro-8-(2,2-dimethylpiperazin-1-ylmethyl)-9-methyl-6-morpholin-4-yl-9H-purine (198 mg, 0.52 mmol), oxetan-3-one (42 mg, 0.58 mmol) and 4 Å powdered molecular sieves in DCE (10 mL) was allowed to stir at r.t for 4 h before the addition of sodium triacetoxyborohydride (144 mg, 0.68 mmol). The resulting mixture was allowed to stir for 16 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (192 mg, 85%). 1H NMR (CDCl3, 400 MHz): δ 4.63 (2 H, t, J=6.48 Hz), 4.55 (2 H, t, J=6.08 Hz), 4.27 (4 H, brd s), 3.84-3.80 (7 H, m), 3.49 (2 H, s), 3.38-3.37 (1 H, m), 2.50-2.40 (2 H, m), 2.23-2.04 (4 H, m), 1.20 (6 H, s)
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]3[CH:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:10]=[CH:9][C:8]2=3)=[CH:3][CH:2]=1.[Br:33]C1CC(=O)NC1=O>C(Cl)(Cl)Cl>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:10][CH:9]=3)[CH2:14][C:15]3[CH:16]=[C:17]([Br:33])[CH:18]=[CH:19][C:20]2=3)=[CH:3][CH:2]=1
Reactant: O=C1CC(Br)C(=O)N1
Reactant: c1ccc(-c2ccc(N3c4ccccc4Cc4cc(-c5ccccc5)ccc43)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Brc1ccc2c(c1)Cc1cc(-c3ccccc3)ccc1N2c1ccc(-c2ccccc2)cc1
Yield: 70 %

Procedure:
10-(biphenyl-4-yl)-2-phenyl-9,10-dihydroacridine (7.8 g, 19.0 mmol) was added with chloroform (300 ml), and with bromosuccinimide (3.7 g, 21.0 mmol). The resultant solution was stirred at room temperature for 2 hours. After the reaction was completed, the resultant solution was washed with distilled water. Then, an organic layer was extracted and dried with sodium sulfate so as to remove the solvent. The residue was purified by silica gel column chromatography (methylene chloride/n-hexane (1/10)) to obtain 10-(biphenyl-4-yl)-2-bromo-7-phenyl-9,10-dihydroacridine compound (pale yellow solid, 6.5 g, yield 70%).