Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[C:6]([C:14]#[N:15])=[CH:5]2.C[O-].[Na+].[Na].[NH3:20]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2=[CH:8][C:7]3[C:12](=[NH:13])[NH:15][C:14](=[NH:20])[C:6]=3[CH:5]=[C:4]2[CH:3]=1
Reactant: N#Cc1cc2ccc(Br)cc2cc1C#N
Reactant: N
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: N=C1NC(=N)c2cc3cc(Br)ccc3cc21

Procedure:
Under nitrogen, 44.1 g (0.172 mol) of 6-bromo-2,3-dicyanonaphthalene was added to a solution of sodium methoxide in methanol prepared by adding 1.92 g (84 mmols ) of metallic sodium in 5 times to 270 ml of absolute methanol, and anhydrous ammonia gas was slowly bubbled into the resulting mixture with sufficient mixing at room temperature for about 1 hour. The mixture was refluxed for about 3 hours, while bubbling therethrough anhydrous ammonia gas. After cooling, the yellow solid precipitated was filtered and the residue was sufficiently washed with methanol and dried under reduced pressure to obtain 45 g of 6-bromo-1,3-diiminobenz[f]isoindoline as a yellow solid. IR specturm of this 6-bromo-1,3-diiminobenz[f]isoindoline is shown in in FIG. 3. The 6-bromo-1,3-diiminobenz[f]isoindoline was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11](Cl)=[N:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:11]2[CH:17]=[C:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2]
Reactant: COc1ccc(C(Cl)=NO)cc1C#N
Reactant: C#CC(=O)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccc(OC)c(C#N)c2)no1
Temperature: 40 °C

Procedure:
3-Cyano-N-hydroxy-4-methoxybenzenecaboximidoyl chloride, ethyl propiolate and triethylamine were dissolved in a THF solution, followed by stirring at 40° C. to obtain ethyl 3-(3-cyano-4-methoxyphenyl)-5-isoxazolecarboxylate. AP: 295.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:27]=[C:28]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)[CH:29]=[CH:30][CH:31]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:50]1([CH2:56][CH2:57][OH:58])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:50]1([CH2:56][CH2:57][O:58][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:27]=[C:28]([N:32]6[S:36](=[O:37])(=[O:38])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:34](=[O:47])[CH2:33]6)[CH:29]=[CH:30][CH:31]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O
Reactant: OCCC1CCCCC1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure L using 2-cyclohexyl ethanol (35 μL, 0.25 mmol) to give 5-{3-[2-{4-[6-(2-cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:30])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[C:9]([CH3:14])[N:8]=1>[OH-].[Na+]>[Cl:6][C:7]1[N:8]=[C:9]([CH3:14])[N:10]=[C:11]([OH:2])[CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(O)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To stirred solution of 13M sulfuric acid (125 mL) at about 0° C., 4,6-dichloro-2-methylpyrimidine (20.0 g, 307 mmol) was added portion wise over about 30 min. The solution was then stirred at about 0° C. for about 1.5 h and the reaction was allowed to warm to ambient temperature over about 1.5 h. The reaction was allowed to stir at RT overnight. The acidic mixture was poured into stirred 6N sodium hydroxide (500 mL) in ice, maintaining the temperature <10° C. and stirred for about 10 min. The white solid was collected and washed with warm water to afford 6-chloro-2-methylpyrimidin-4-ol 40.2 g (91%) 1H NMR (400 MHz, DMSO) δ: 12.85 (brs, 1H), 6.34 (s, 1H), 2.30 (s, 3H). LC/MS (Table 1, Method d) Rt=0.74 min; MS m/z: 145.1 (M+H).
Reaction SMILES: [CH:1]1([C@@H:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[CH:7]=2)[NH2:5])[CH2:3][CH2:2]1.C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:1]1([C@H:4]([NH:5][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)c1cccc([C@@H](N)C2CC2)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](c3cccc(C(C)C)c3)C3CC3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 1-2, Example 19, using (S)-cyclopropyl(3-isopropylphenyl)methanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[H-].[Na+].Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(OCC)(=O)C>CN(C=O)C>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1C(=O)C(C)(C)c2cc(C3=NNC(=O)SC3C)ccc21
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
1.16 g 5-(3,6-Dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (Example 3) in 30 ml DMF were cooled to 0° C. 0.175 g sodium hydride from a 55% dispersion in mineral oil was added and the mixture was successively stirred for 0.5 hr at 0° C. and 0.5 hr at 20° C. After cooling to 0° C. a solution of 0.43 g ethyl chloroformate in 2 ml DMF was added dropwise. The reactional mixture was stirred at room temperature for 16 hrs, 250 ml ethyl acetate were added and the organic solution was washed with water. The aqueous phase was extracted with 2×100 ml methylene chloride and the organic solutions were mixed, dried on magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica (methylene chloride-ethyl acetate: 4/1) then washed with isopropyl ether to yield 1.11 g of crystals.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2cccc3c2oc2ccccc23)cc1
Yield: 78.2 %

Procedure:
To a mixture of dibenzofuran-4-boronic acid (40 g, 0.19 mol), 4-bromobenzonitrile (34 g, 0.19 mol), sodium carbonate (120 g) in toluene (500 mL) and water (500 mL) was added tetrakis (triphenylphosphine)palladium (0) (11 g, 0.0095 mol) with stirring under N2 atmosphere. The reaction mixture was refluxed for 20 h. Toluene layer was separated, washed with water, dried and concentrated. The crude product was purified by column chromatography over silica gel (chloroform) to give the title compound (40 g, 79%).
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[O:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1ncccc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2N2CCOCC2)cc1
Temperature: 120 °C

Procedure:
To a 25 mL round-bottomed flask were added 4-(2-fluoropyridin-3-yl)morpholine (0.523 g, 2.87 mmol), 4-aminophenol (0.451 g, 2.88 mmol), cesium carbonate (1.18 g, 3.45 mmol) and DMSO (5 mL). The reaction mixture was heated at 120° C. for 8 h. After cooling to room temperature, the reaction mixture was filtered through SCX cartridges, and rinsed with DCM, MeOH, and 2.0 ammonia in MeOH. The ammonia rinses were combined and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% MeOH in CH2Cl2, to provide 4-(3-morpholinopyridin-2-yloxy)benzenamine. MS: [M+1]=272.1
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH3:25])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:23]#[N:24])[CH2:5]1.[O:26]=[C:27]1[CH2:32][S:31][C:30]2[CH:33]=[CH:34][C:35]([CH:37]=O)=[N:36][C:29]=2[NH:28]1>CO.C(Cl)Cl>[CH3:25][C:4]1([CH2:3][NH:2][CH2:37][C:35]2[CH:34]=[CH:33][C:30]3[S:31][CH2:32][C:27](=[O:26])[NH:28][C:29]=3[N:36]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:23]#[N:24])[CH2:5]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(C#N)c(CCN3CCC(C)(CN)C3)c2c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(C#N)c(CCN3CCC(C)(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2c1
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To a solution of the HCl salt of 4-{2-[3-(aminomethyl)-3-methyl-1-pyrrolidinyl]ethyl}-6-(methyloxy)-3-quinolinecarbonitrile (50 mg) in MeOH (2 mL) and DCM (2 mL) were added NaHCO (130 mg, 1.6 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (30 mg, 0.18 mmol). After 24 h at 25° C., NaBH (10 mg, 0.27 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM-H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO, concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1% NH OH)) yielding the title compound (20 mg) as a brown oil: LC/MS (ES) m/e 503 (M+H) 1H NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.35 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.12 (s, 3H), 3.83 (s, 2H), 3.51 (m, 3H), 2.9-2.5 (m, 6H), 2.3 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.1 (s, 3H).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.C[O-].[Na+].[NH2:14][C:15]1[C:24]([C:25]([NH2:27])=[O:26])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1>>[N:14]1[C:15]2[C:24](=[CH:23][C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:16]=2)[C:25](=[O:26])[NH:27][C:2]=1[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1cc2ccccc2cc1N
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)c1nc2cc3ccccc3cc2c(=O)[nH]1
Yield: 79 %

Procedure:
Diethyl oxalate (2.35 g., 16.1 millimoles), sodium methoxide (10 mg) and 2-aminonaphthalene-3-carboxamide (1.50 g., 8.05 millimoles) are mixed together and heated at reflux for two days. The mixture is then cooled in an ice bath and the brown precipitate recovered by filtration. It is recrystallized from ethanol to give 1.76 g. (79% yield) of the desired ester. M.P. 240°-242° C.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[Cl:30][C:31]1[C:32]([NH2:41])=[N:33][CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1.CCN=C=NCCCN(C)C.Cl.C1COCC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:30][C:31]1[C:32]([NH:41][C:20]([C:19]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2/[CH:11]=[CH:10]/[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:29])[F:1])[C:5]=2[O:23][CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:21])=[N:33][CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=1
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2ncc(C(F)(F)F)cc2Cl)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 3-chloro-5-(trifluoromethyl)pyridin-2-amine (51 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol) and DMAP (27 mg, 0.236 mmol) in the mixture of THF and DMF (1:1, 6 mL) to give 25 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 3.57 (s, 2H), 7.16 (t, J=73.5 Hz, 1H), 7.20-7.46 (m, 3H), 7.53-7.62 (m, 2H), 7.88 (d, J=15.9 Hz, 1H), 8.09 (s, 1H), 8.57 (s, 1H), 8.86 (s, 1H), 11.12 (br s, 1H); APCI-MS (m/z) 601.30 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:6].[CH3:19]COCC.C[Mg]Br>O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]([C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[O:2][CH3:1])([OH:6])[CH3:19]
Reactant: COc1ccccc1C(=O)c1ccccc1OC
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: O
Product: COc1ccccc1C(C)(O)c1ccccc1OC
Temperature: 25 °C

Procedure:
2,2'-Dimethoxybenzophenone (24.2 g, 0.14 mole) and 400 ml of ether were placed in a 1 l flask and stirred at ambient temperature and methyl magnesium bromide (40 ml of 3.0M solution in ether) was added dropwise. The resulting mixture was stirred overnight and then a few ml of water were added to quench the Grignard reagent. About 300 ml of ethyl acetate and 250 ml of 10 percent hydrochloric acid were then added and the mixture was shaken. The organic layer was next recovered, extracted with 100 ml of water and 100 ml of saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 25.6 g (98 percent of theory) of the title compound as a white solid melting at 122°-123° C. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.C(Cl)[Cl:15].C(Cl)(=O)C(Cl)=O.CN(C=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([Cl:15])=[O:13])[N:10]=2)[N:7]=1
Reactant: ClCCl
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 250-mL, round-bottomed flask was added 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid (2.0 g, 10 mmol, Maybridge, Cornwall, UK) and CH2Cl2 (40 mL). To the mixture was added oxalyl chloride (20 mL, 40 mmol, 2 M in CH2Cl2) and DMF (8.0 μL, 0.10 mmol). The mixture was stirred for 1.5 h at 25° C. Toluene (10 mL) was added and the mixture was concentrated to afford the title compound which was taken on to the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])=[C:23]([C:24]([N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][CH:6]=3)[CH2:11]2)=[O:25])[CH:27]=1)(=[O:18])=[O:17]
Reactant: FC(F)(F)c1cccc2c1CNCC2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cccc(C(F)(F)F)c2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2). MS (m/e): MS (m/e): 496.4 (M+H+).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])[CH2:9][CH2:10]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:26].[Na+]>CC(C)=O>[CH2:1]([N:8]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])[CH2:9][CH2:10][I:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCCN(Cc1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1N(CCI)Cc1ccccc1
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A mixture of methanesulphonic acid 2-[benzyl-(4-bromo-2-nitro-phenyl)-amino]-ethyl ester (25 g, Reference Example 8) and sodium iodide (16.23 g) in anhydrous acetone (100 ml) was heated at reflux for 4 hours when a further portion of sodium iodide (8.12 g) was added and refluxing was continued for a further 16 hours. The reaction mixture was evaporated under reduced pressure (2.7 kPa) at 40° C. and the residue was treated with distilled water (200 ml). The resulting mixture was extracted three times with dichloromethane (150 ml). The combined organic extracts were dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting brown oil (29,16 g) was subjected to flash chromatography on silica (0,040-0,063 mm) eluting with a mixture of cyclohexane and ethyl acetate (9:1, v/v) to give the title compound (23.55 g) as a yellow oil. 1H NMR, 300 HMz, (CD3)2SO: δ3.3 (m, 4H); 4.4 (s, 2H); 7.25(m, 5H); 7.4 (d, J=8 Hz, 1H); 7.6 (dd, J=8 Hz and J=1.5 Hz, 1H); 8 (d, J=1.5 Hz, 1H). MS (EI): M+ 462 and 460 (5%), 445 and 443 (20%), 321 and 319 (10%), 91 (100%).
Reaction SMILES: [C:1]([C:5]([Br:8])(Br)[Br:6])([F:4])([F:3])[F:2].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].O>CN(C=O)C.[Zn]>[Br:6][C:5]([Br:8])([C:1]([F:4])([F:3])[F:2])[CH:12]([C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=1[Cl:9])[OH:13]
Reactant: FC(F)(F)C(Br)(Br)Br
Reactant: O=Cc1ccccc1Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: OC(c1ccccc1Cl)C(Br)(Br)C(F)(F)F
Reaction time: 6 h

Procedure:
83.5 g of CF3CBr3 in anhydrous DMF and 28 g of 2-chlorobenzaldehyde were reacted under a nitrogen atmosphere. The mixture was brought to 5° C. and zinc in powder (g.16.0) was added to it slowly. Then the mixture was let reach the room temperature and kept under stirring for 6 hours. The mixture was poured into water and extracted three times with ethyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:18].FS(O[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[Cl:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]=1[NH:1][CH3:24]
Reactant: Nc1c(Cl)ccc2c1C(=O)c1ccccc1C2=O
Reactant: COS(=O)(=O)F
Solvent: Cc1ccccc1
Product: CNc1c(Cl)ccc2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h

Procedure:
A solution of 1-amino-2-chloroanthraquinone (2.6 grams; 0.01 mole) and methyl fluorosulfonate (1.254 grams; 0.011 mole) in toluene (50 mls) was refluxed for 22 hours and filtered while hot. The residue in the flask was combined with the filter cake and the combined solids were slurried in 5 N sodium hydroxide at 25° C. for 0.5 hour. The slurry was then filtered, and the solid was rinsed with water and dried. The yield of product obtained was 41% of theoretical.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[N:14][CH:15]=1)=O.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:42])[CH3:41])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[K+].[ClH:45]>CCO>[ClH:45].[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:35]=[CH:36][C:37]([C:40](=[O:42])/[CH:41]=[CH:8]/[C:10]3[CH:15]=[N:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=3)=[CH:38][CH:39]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1ccc(/C=C/C(=O)O)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid trifluoroacetate (272 mg, 0.93 mmol), 4-(4-acetyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (obtained as described in Preparation 9, 283 mg, 0.93 mmol) and 1.7 M KOH (0.820 ml) in EtOH (10 ml) was stirred at 0° C. for 8 h and then at room temperature for 6 days. The mixture was acidified with 10% HCl until reaching a pH value of 3 and the resulting precipitate was filtered to give 184 mg of 4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester hydrochloride.