Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Cc1cccnc1N
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ncccc2C)c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 26.8 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 2-amino-3-methylpyridine (45 mg, 0.417 mmol) was added portionwise. The resulting mixture was stirred at room temperature for five days. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield the title compound (26 mg, 27% yield).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[O:12])[CH:5]=1)(=[O:3])[CH3:2].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH:2]=[CH:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[N:9]=[C:8]([CH3:10])[N:7]=2)=[O:12])=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: O=Cc1cccnc1
Reactant: COc1cc(CNC(=O)c2cc(C(C)=O)nc(C)n2)ccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(CNC(=O)c2cc(C(=O)C=Cc3cccnc3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
To a cold solution of 6-acetyl-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.050 g, 0.158 mmol, Preparation #23) and nicotinaldehyde (0.0168 mg, 0.158 mmol) in DCM (2 mL) was added aluminium chloride (0.02311 g, 0.173 mmol). The reaction mixture was allowed to stir for 15 minutes and added TEA (0.033 mL, 0.236 mmol). The reaction mixture was slowly warmed to RT and stirred for 3 h. The reaction mixture was heated to about 50° C. for 0.5 h then cooled to RT and poured into cold water (20 mL) and the product was extracted with diethyl ether (2×20 mL). The organic layer was washed successively with water (1×20 mL), brine (1×20 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by preparative TLC eluting with 50% EtOAC/hexane to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(3-(pyridin-3-yl)acryloyl)pyrimidine-4-carboxamide 0.015 g, (23.42%), 1H NMR (400 MHz, DMSO): δ 9.59 (bs, 1H) 9.00 (s, 1H) 8.67 (s, 1H) 8.33-8.17 (m, 3H) 8.00-7.96 (m, 1H) 7.52-7.51 (m, 1H) 7.19-7.17 (m, 2H) 6.92-6.91 (m, 1H) 4.51-4.49 (m, 2H) 3.82 (s, 3H) 2.89 (s, 3H), MS m/z: 407 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1.ClC(Cl)(Cl)C#N.C(N(CC)CC)C.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:21]([NH:49][C:46]5[CH:47]=[CH:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=5)=[O:22])=[CH:24][CH:25]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1
Reactant: O=C1Cc2cnc(Nc3ccc(C(=O)O)cc3)nc2-c2ccc(Cl)cc2N1
Reactant: COc1ccc(N)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(Nc3ncc4c(n3)-c3ccc(Cl)cc3NC(=O)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a pre swelled PL-TPP resin [200 mg, 0.3 mmol, (Polymer labs, 1.5 mmol/gram loading)] in DMA (1.0 mL) was added a mixture of 4-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic acid (I-3) (25 mg 0.066 mmol), DMA (1.5 mL) and trichloroacetonitrile (0.53 mmol). After agitating for three hours at room temperature, triethylamine (46 μL, 0.33 mmol) was added, followed by p-anisidine (8.1 mg, 0.066 mmol). The reaction mixture was stirred at 22° C. overnight. The reaction mixture was filtered and the resin was washed with DMF, DMA, and MeOH (1×1 mL). The combined organic layers were concentrated and the crude product was purified by RP-HPLC using an Agilent HPLC equipped with a SunFire™ column (Waters Corporation), Method Formic Acid, to give I-555 (22 mg, 69%). 1H NMR (DMSO): δ 10.38 (s, 1H), 10.32 (s, 1H), 9.93 (s, 1H), 8.59 (s, 1H), 8.10 (d, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.64 (d, J=9.3 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.29 (s, 1H), 6.89 (d, J=8.5 Hz, 1H), 3.73 (s, 2H), 3.43 (s, 1H), 3.32 (s, 3H); MS Rt=2.70 min (m/z) 466 (M+1).
Reaction SMILES: C(OC(=O)COC1C=CC(SCC2C=C(C3C=CC(C(F)(F)F)=CC=3)OC=2)=CC=1C)C.[OH:32][C:33]1[CH:47]=[CH:46][C:36]([O:37][C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:48])[CH:34]=1.[C:49]1([CH:55]([C:57]2[CH:61]=[C:60]([C:62]3[CH:67]=[CH:66][C:65]([C:68]([F:71])([F:70])[F:69])=[CH:64][CH:63]=3)[S:59][CH:58]=2)O)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH3:44][C:38]([O:37][C:36]1[CH:46]=[CH:47][C:33]([O:32][CH:55]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:57]2[CH:61]=[C:60]([C:62]3[CH:63]=[CH:64][C:65]([C:68]([F:69])([F:70])[F:71])=[CH:66][CH:67]=3)[S:59][CH:58]=2)=[CH:34][C:35]=1[CH3:48])([CH3:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: OC(c1ccccc1)c1csc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(c2ccccc2)c2csc(-c3ccc(C(F)(F)F)cc3)c2)cc1C

Procedure:
The title compound was prepared by a method analogous to that used for the preparation of ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate (example 1) using ethyl 2-(4-hydroxy-2-methylphenoxy)-2-methylpropanoate (intermediate 10) and phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methanol (intermediate 127).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH3:21])[CH:14]=[C:13]2[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34])=[O:9].[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1.Cl>C(Cl)Cl.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[C:38]([CH:37]1[CH2:36][C:35](=[O:41])[O:9][CH:8]1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH3:21])[CH:14]=[C:13]2[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34])([OH:40])=[O:39]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C3OC(=O)CC3C(=O)O)ccc21
Reaction time: 15 h

Procedure:
Triethylamine (8.32 g) was added slowly to a stirred mixture of methyl 4-[5-formyl-1-propylindol-3-ylmethyl]-3-methoxybenzoate (10 g), succinic anhydride (5.5 g) and zinc chloride (11.4 g) in methylene chloride (50 ml), under a nitrogen atmosphere, such that the temperature of the reaction did not exceed 25°. After complete addition, the mixture was stirred for 15 hr, poured into a mixture of 2M hydrochloric acid (500 ml) and ethyl acetate (500 ml), the layers separated and the aqueous layer extracted with ethyl acetate. The combined extracts were washed (water (three times), brine), dried (MgSO4) and evaporated. The product was dissolved in aqueous sodium bicarbonate (300 ml, 6% w/v), and the solution extracted with ether. The aqueous layer was neutralized with 6M hydrochloric acid, acidified to pH 4 with 1M hydrochloric acid, and extracted with ethyl acetate. The extracts were washed (water (twice), brine), dried (MgSO4) and evaporated to give methyl 4-[5-(3-carboxy-2,3,4,5-tetrahydro-5-oxofuran-2-yl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (12.36 g, 97%, as a mixture of diastereomers) as an off-white foam: partial NMR (300 MHz, DMSO-d6): 0.83(m, 3H, CH3, both isomers), 3.83(s, 3H, OCH3, both isomers), 3.91(s, 3H, OCH3, both isomers), 5.61(d, 0.5H, CHOC(O), isomer A), 5.87(d, 0.5H, CHOC(O) isomer B).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[N:11][C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH3:23].CC#N.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH2:27]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[S:13][C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[N:11][C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH3:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(C=C2SC(N3CCN(C)CC3)=NC2=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C=C2SC(N3CCN(C)CC3)=NC2=O)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 28 %

Procedure:
To a N2-purged flask was added ′5-[1-(4-Hydroxy-3-methoxy-phenyl)-methylidene]-2-(4-methyl-piperazin-1-yl)thiazol-4-one (57 mg, 0.17 mmol), MeCN (5 mL), benzyl chloride (30 μL, 1.5 equiv), and K2CO3 (70 mg, 3 equiv). The reaction mixture was stirred at 70° C. for 6 h. The reaction mixture was diluted with EtOAc (100 mL), and the excess K2CO3 was removed by filtration through a fritted glass funnel. The product solution was washed with aq NH4Cl (50 mL×2) and H2O (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was chromatographed (SiO2, DCM/MeOH 100:0 to 92:8) to provide pure title compound (20 mg, 28% yield). 1H NMR (DMSO-d6) δ 7.66 (1H, s), 7.44-7.52 (5H, m), 7.29 (1H, s), 7.23-724 (2H, m), 5.22 (2H, s), 3.96 (2H, t, J=4.6 Hz), 3.89 (3H, s), 3.70 (2H, t, J=4.6 Hz), 2.48-2.52 (4H, m), 2.29 (3H, s); MS (ESI) 424 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([N:27]([CH3:44])[C:28]([C:30]2[N:34]([CH3:35])[N:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=2[C:40]([F:43])([F:42])[F:41])=[O:29])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl.C(OCC)(=O)C>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([N:27]([CH3:44])[C:28]([C:30]2[N:34]([CH3:35])[N:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[C:31]=2[C:40]([F:41])([F:42])[F:43])=[O:29])=[CH:23][C:19]=1[C:20](=[O:21])[NH:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1
Reactant: N#CC1(N)CC1
Reactant: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)F)nn1C)c1ccc(Cl)c(C(=O)Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)F)nn1C)c1ccc(Cl)c(C(=O)NC2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
68.3 mg (0.58 mmol) of 1-aminocyclopropanecarbonitrile hydrochloride are initially charged in 5.0 ml of dichloromethane p.a., and 0.148 ml (0.86 mmol) of N-ethyldiisopropylamine and 156 mg of 2-chloro-5-(methyl{[1-methyl-3,4-bis(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoyl chloride (0.29 mmol) dissolved in 5.0 ml of dichloromethane p.a. are then added in succession. The reaction is stirred at room temperature for 16 hours. The reaction solution is diluted with 30 ml of ethyl acetate. The organic phase is washed twice with 1 N hydrochloric acid, once with 1 N aqueous sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and filtered and the solvent is removed on a rotary evaporator under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=2[Cl:28])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC1N=C(OC)N=C(OC)[N:32]=1.CN1CCOCC1.[NH4+].[OH-]>C1COCC1.O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:32])=[O:24])=[CH:21][C:20]=2[Cl:28])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccc(C(=O)O)cc1Cl
Reactant: COc1nc(Cl)nc(OC)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
4-[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoic acid (0.5 g, 1.03 mmol) was taken up in THF (10 ml). 2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.22 g, 1.24 mmol) and N-methyl morpholine (0.34 ml, 3.09 mmol) were added. The mixture stirred at room temperature for 1 hour. At this time, NH4OH (2.5 ml) was added and the reaction stirred at room temperature for one more hour. To the reaction mixture was added more THF (50 ml) and water (200 ml). The mixture was extracted with ethyl acetate. The ethyl acetate extraction was washed with saturated brine solution. The brine layer was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and the resulting precipitate was collected on a filter pad to yield a white powder (0.38 g, 76%) 1H NMR (300 MHz, CD3OD) δ 8.18 (d, J=1.81 Hz, 1H), 8.02 (dd, J=8.26, 2.01 Hz, 1H), 7.69 (app q, J=8.26 Hz, 1H), 7.55 (d, J=8.06 Hz, 1H) 7.12-7.06 (m, 2H), 6.71 (s, 1H), 5.40 (s, 2H), 2.07 (s, 3H). ES MS m/z 482 (M+H). ES-HRMS m/z 482.9919 (M+H calcd for C20H15BrClF2N2O3 requires 482.9917).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Br)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[CH3:27][NH:28][CH3:29].[I-].[Na+]>>[CH3:27][N:28]([CH2:17][C:14]1[N:13]2[C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:26][C:8]=3[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:10][CH2:11][C:12]2=[N:16][N:15]=1)[CH3:29]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CBr)n1-2
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Product: CN(C)Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 8-nitro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine was reacted with dimethylamine in the presence of sodium iodide to give 1-[(dimethylamino)methyl]-8-nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:6][NH:7][C:8]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([CH3:17])[N:11]=1)=[O:9].[CH3:27]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]1[CH:18]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:25])[F:26])[CH:20]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([CH3:17])[N:11]=1)=[O:9]
Reactant: Cc1ncc(Br)c(C(=O)NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: ClCCl
Product: Cc1ncc(Br)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 2.28 g (5 mmol) 5-bromo-2-methyl-pyrimidine-4-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide in 20 ml N,N-dimethylformamide 0.26 g (5.5 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.4 ml (6.5 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 80 ml H2O, 80 ml brine and 80 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 80 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 19:1) to give 1.98 g (87%) 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a waxy solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4](S(C)=O)[N:3]=1.[CH3:14][C:15]1[C:16]([CH2:21][OH:22])=[N:17][CH:18]=[CH:19][CH:20]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([O:22][CH2:21][C:16]2[C:15]([CH3:14])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(Cl)c1C#N
Reactant: Cc1cccnc1CO
Solvent: O
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccnc1COc1nc(N)nc(Cl)c1C#N
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To a stirred suspension of 50 mg (0.23 mmol) 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile in 1 ml DME were added 28 mg (0.23 mmol) 3-methyl-2-pyridinemethanol and 521l (0.35 mmol) DBU and stirring continued for 30 min at room temperature. 5 ml water was then added and the resulting crystals collected by filtration and washed with ether to afford 22 mg (35%) 2-amino-4-chloro-6-(3-methyl-pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 278 (M{37Cl}+H+, 35), 276 (M{35Cl}+H+, 100).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[CH3:17][N:18]1[C:27](/[CH:28]=[CH:29]/[CH:30]=[O:31])=[C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:38].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C.O.C(OCC)C>[OH:31][CH:30](/[CH:29]=[CH:28]/[C:27]1[N:18]([CH3:17])[C:19](=[O:38])[C:20]2[C:25]([C:26]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Cn1c(/C=C/C=O)c(-c2ccccc2)c2ccccc2c1=O
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccccc2)c2ccccc2c(=O)n1C
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
A stirred suspension of sodium hydride (0.078 g; 80% dispersion in mineral oil) in dry tetrahydrofuran (10 ml) under an atmosphere of nitrogen and at -10° C. was treated with ethyl acetoacetate (0.312 g), dropwise, during 5 minutes. The mixture was stirred for 30 minutes and then it was treated with a solution of butyl lithium in hexane (1 ml; 2.5M) during a period of 5 minutes, whilst maintaining the temperature at -10° C. The mixture was stirred for a further period of 20 minutes at -10° C. and then treated with a solution of (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)propenal (0.34 g) in dry tetrahydrofuran (30 ml), dropwise, during 15 minutes at -10° C. The mixture was stirred at -10° C. for 2 hours and the resulting red-brown solution was treated with saturated aqueous ammonium chloride solution (15 ml) and then it was poured into a mixture of diethyl ether (75 ml) and water (50 ml). The organic phase was separated and the aqueous phase was extracted with diethyl ether (50 ml). The combined organic phases were washed with water (3×50 ml), dried over magnesium sulphate and evaporated, to give a yellow solid which was subjected to flash chromatography on silica gel, using ethyl acetate as eluent, to give ethyl (E)-5-hydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)-3-oxohept-6-enoate (0.35 g) in the form of a yellow solid, m.p.148°-149° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([F:25])[F:24].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:22][C:23]([F:25])([F:24])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: FC(F)(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OCC(F)(F)c2ccccc2)C1
Temperature: 180 °C
Yield: 40.9 %

Procedure:
The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), (2-bromo-1,1-difluoro-ethyl)-benzene (1 mmol), and K2CO3 (1 mmol) in acetonitrile (3 mL) was heated at 180° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (90 mg). To this compound was added CH2Cl2 (20 mL) and CF3COOH (3 mL). The mixture was stirred at rt for 4 h and concentrated to give the title compound (50 mg). MS (ESI): mass calcd. for C17H16ClF2NO2, 339.1; m/z found, 340.0 [M+H]+. 1H NMR (MeOD): 7.66-7.46 (m, 5H), 7.02-6.83 (m, 3H), 5.05-4.95 (m, 1H), 4.50 (t, J=12.7 Hz, 2H), 4.30-4.20 (m, 2H), 4.10-3.98 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([Br:9])=[C:7]([CH3:10])[NH:6][C:5](=[S:11])[N:4]=1.[OH-].[K+].I[CH2:15][C:16]([NH2:18])=[O:17]>>[C:16]([CH2:15][S:11][C:5]1[N:6]=[C:7]([CH3:10])[C:8]([Br:9])=[C:3]([CH3:2])[N:4]=1)(=[O:17])[NH2:18]
Reactant: Cc1nc(=S)[nH]c(C)c1Br
Reactant: NC(=O)CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(SCC(N)=O)nc(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
4,6-Dimethyl-5-bromopyrimidine-2-thione HCl salt (5 mmol) was added to ethanolic (60 ml) KOH (11.4 mmol), the solution stirred for 10 min at room temperature, iodoacetamide (5.7 mmol) added, the stirring continued for 20 min at room temperature and for 100 min at 70° C. (pH 8). The warm reaction mixture was filtered, the filtrate evaporated, the residue extracted with chloroform (150 ml), the chloroform solution washed and the dried (MgSO4) solution evaporated to leave the sulfide; yield 72%, m.p. 175°-177° C. (iPrOH). 1H NMR (DMSO-d6): δ2.50 (Me), 3.80 (SCH2).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].[CH:30]1[C:43]2[C:34](=[N:35][C:36]3[C:41]([C:42]=2[NH:44][C:45]2[CH:46]=[C:47]([CH2:52][OH:53])[CH:48]=[C:49]([NH2:51])[CH:50]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1>>[CH:30]1[C:43]2[C:34](=[N:35][C:36]3[C:41]([C:42]=2[NH:44][C:45]2[CH:50]=[C:49]([NH:51][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:7])[CH:48]=[C:47]([CH2:52][OH:53])[CH:46]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(F)c3)CC2)cc1C(=O)O
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(F)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 72.1 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3-fluorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:16])[CH:10]=1)([O-])=O.[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]3[NH:21][C:20]4[CH:19]=[CH:18][C:6]([NH:7][C:8](=[O:17])[C:9]5[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:16])[CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cc(O)cc(O)c1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1cc(O)cc(O)c1

Procedure:
Compound 425 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(3,5-dihydroxybenzoyl)aniline and 4-morpholinobenzaldehyde. [M+H]+ calcd for C24H22N4O4: 431.17; found: 431.18.