Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23]C)=[C:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:17]=1[CH3:35])[C:9](=[O:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[CH2:1]([N:8]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[C:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:17]=1[CH3:35])[C:9](=[O:15])[CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C)c(N(Cc2ccccc2)C(=O)CC(C)(C)C)c(C)c1Cc1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(O)c(Cc2ccc(C(C)C)cc2)c(C)c1N(Cc1ccccc1)C(=O)CC(C)(C)C
Yield: 83 %

Procedure:
Using N-benzyl-N-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimethylbutanamide obtained in Reference Example 332, the title compound was synthesized in the same manner as in Reference Example 335. Yield 83%. Melting point: 167-168° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(O)C2)C(=O)Nc2cnccn2)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxy-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 38, 60 mg, 0.142 mmol) in methylene chloride (10 mL) was treated with Dess-Martin periodinane (132.5 mg, 0.312 mmol). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then diluted with methylene chloride (10 mL) and washed with a 1M aqueous citric acid solution (10 mL). The pH of the aqueous layer was adjusted to 5. The aqueous layer was then extracted with methylene chloride (20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50–100% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (45 mg, 75%) as an off-white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[Cl:11]>CC(O)=O.[Zn]>[Cl:11][C:3]1[CH:4]=[C:5]([S:7]([NH2:10])(=[O:9])=[O:8])[S:6][CH:2]=1
Reactant: NS(=O)(=O)c1cc(Cl)c(Br)s1
Agent: [Zn]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(Cl)cs1
Temperature: 120 °C
Reaction time: 6 h
Yield: 51.2 %

Procedure:
To a stirred solution of 5-bromo-4-chlorothiophene-2-sulfonamide (2.4 g, 8.7 mmol) in AcOH (20 mL) is added zinc dust (1.7 g, 26.0 mmol). The reaction mixture is heated to 120° C. for 6 hr. After 6 hr, the mixture is filtered and neutralized with 1 M NaOH. The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic extracts are dried (Na2SO4), filtered and concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with CH2Cl2 to afford the title compound (0.88 g, 52%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[CH:35]=[CH:34]2>>[CH3:40][N:36]1[CH:35]=[CH:34][C:33]2[C:38](=[C:29]([NH:28][C:2]3[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:26][CH:27]=4)[N:3]=3)[CH:30]=[CH:31][CH:32]=2)[C:37]1=[O:39]
Reactant: Cn1ccc2cccc(N)c2c1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4ccn(C)c(=O)c34)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (203.1 mg, 0.4793 mmol) and 8-amino-2-methylisoquinolin-1(2H)-one (Compound 131A, 100.0 mg, 0.5740 mmol). The crude product was purified using the Teledyne/ISCO Combiflash system, eluting with 0-5% MeOH:CH2Cl2. The desired fractions were pooled together and concentrated in vacuo, yielding the title material as a yellow solid, 225.9 mg (82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.23 (br s, 1H), 9.88 (s, 1H), 8.87 (br s, 1H), 8.48 (s, 1H), 7.55-7.68 (m, 3H), 7.53 (d, J=7.1 Hz, 1H), 7.31 (d, J=7.1 Hz, 1H), 7.24 (dd, J=8.6, 2.3 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 3.91-4.01 (m, 4H), 3.53 (s, 3H), 3.20 (d, J=21.2 Hz, 2H), 1.18 (t, J=6.9 Hz, 6H). MS (ES+): m/z 562.11 (100) [MH+]. HPLC: tR=3.58 min (ZQ3, polar—5 min).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>C(Cl)Cl>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:27]
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)c1ccco1
Yield: 87.3 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride, 0.49 ml (4.98 mmol) of 2-furoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 950 mg of the desired compound (yield: 87.3%, colorless powder). mp: 98.0°-99.0° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](S(C)(=O)=O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>CCOCC>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(S(C)(=O)=O)nc(=O)c1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCc1[nH]n(C2CCCC2)c2nc(Nc3ccccc3)nc(=O)c1-2
Temperature: 185 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(methylsulfonyl) pyrazolo[3,4-d]pyrimidin-4-one (2.3 g, 7.4 mmol) and aniline (1.2 g, 13 mmol) was heated at 180-190° C. for 3 hours. The reaction mixture was cooled to room temperature and allowed to stand at room temperature overnight. Ether was added to the reaction mixture and the product was collected by filtration, washed with ether and dried at 80-85° C. in a vacuum oven to afford crude product. The crude product was treated with saturated NaHCO3 (25 mL) and the insoluble material was collected by filtration, dissolved in hot isopropanol, treated with charcoal and concentrated in vacuo. The residue was crystallized from ether and dried at 80-85° C. in a vacuum oven to afford 0.58 g (25%) of 1-cyclopentyl-3-ethyl-6-(phenylamino)pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:35]2=[O:48])=[C:30]([OH:49])[CH:29]=1>>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH2:5][OH:16])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:35]2=[O:48])=[C:30]([OH:49])[CH:29]=1
Reactant: CCCCCN1C(=O)C(c2ccc(Br)cc2O)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(CO)(c2ccc(Br)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4-bromo-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained: Rf=0.5 (EtOAc/Hexanes, ¼).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.O1CCCC1.C(O)C.O.[OH-].[Li+]>O>[F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(F)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2cc(F)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (8 g; 44.4 mmol) was mixed with tetrahydrofuran (225 mL), ethanol (110 mL) and water (55 mL). Lithium hydroxide monohydrate (0.962 g; 22.9 mmol) was added. The mixture was stirred at ambient temperature overnight. The mixture concentrated under reduced pressure to remove tetrahydrofuran and ethanol. Hydrochloric acid (2N) was added to aqueous mixture to adjust to pH 3. White precipitate formed and was filtered off with drying under high vacuum overnight to give 7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid as a white solid (6.3 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:37][C:38]1[S:39][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(OCC)(=O)C>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:40]4[S:39][C:38]([Cl:37])=[N:42][CH:41]=4)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC1(C)OB(c2cnc(Cl)s2)OC1(C)C
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc(Cl)s3)nc12)C(=O)N1CCC(C#N)CC1
Temperature: 170 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
In a microwave vial, 1,4-dioxane (3 mL) was purged with argon gas. 2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (100 mg, 0.173 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (128 mg, 0.519 mmol), palladium tetrakis(triphenylphosphine) (10 mg, 0.009 mmol), and then cesium carbonate (113 mg, 0.346 mmol) were added. The reaction vessel was sealed and heated in a microwave reactor at 170° C. for 1 h. Additional 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (90 mg, 0.366 mmol) and palladium tetrakis(triphenylphosphine) (6 mg, 0.005 mmol) were added and the reaction was resubjected at 170° C. for 2 h. The reaction was cooled and water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to yield 39 mg (36%) of 2-(2-chlorothiazol-5-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide. (M+Na)+=638.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Cl)[CH:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:22]([C:29]1[CH:30]=[CH:31][C:32](=[O:35])[NH:33][N:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][N:33]2[C:32](=[O:35])[CH:31]=[CH:30][C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:34]2)=[N:6][CH:7]=1
Reactant: O=c1ccc(Oc2ccccc2)n[nH]1
Reactant: ClCc1cccc(-c2ncc(Br)cn2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(Oc2ccccc2)nn1Cc1cccc(-c2ncc(Br)cn2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.3 2.59 g (9.14 mmol) of 5-bromo-2-(3-chloromethylphenyl)pyrimidine and 2.84 g (8.70 mmol) of caesium carbonate are added to a suspension of 1.64 g (8.70 mmol) of 6-phenoxy-2H-pyridazin-3-one in 17.5 ml of DMF, and the mixture is stirred at room temperature for 18 hours. Water is added to the reaction mixture. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving 2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-phenoxy-2H-pyridazin-3-one as colourless crystals; ESI 435, 437.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(OC([C:11]1C=C(C(OCC)=O)[NH:13][N:12]=1)=O)C.BrC[CH2:23][Cl:24].BrCCBr>>[N:4]1([CH2:3][CH2:23][Cl:24])[CH:5]=[CH:11][N:12]=[N:13]1.[NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: ClCCBr
Agent: c1nc[nH]n1
Solvent: BrCCBr
Product: ClCCn1ccnn1

Procedure:
When an equivalent amount of 1,2,4-triazole is substituted for 3,5-diethoxycarbonyl-1H-pyrazole and an equivalent amount of 2-bromochloroethane is substituted for 1,2-dibromoethane in the procedure of Example 4, 2-(1-H-triazol-1-yl)ethyl chloride is isolated 1,2,4-triazole, Aldrich, 43%, used directly after workup).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18].N#N>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:17]=[CH2:18])=[N:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: C1COCCO1
Product: C=Cc1ccc(CO[Si](C)(C)C(C)(C)C)cn1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A solution of 2-bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (1.0 g, 3.3 mmol) and vinyltributylstannane (2.09 g, 6.6 mmol) in 1,4-dioxane (30 ml) was degassed with a stream of N2 for 15 min and then Pd(PPh3)2Cl2 (116 mg, 5 mol %) was added and the reaction mixture heated at reflux under N2 for 20 h. After cooling to room temperature, the solvent were removed under reduced pressure and the mixture was azeotroped with xylene (2×10 ml). The residue was purified by column chromatography on silica using 20% EtOAc/iso-hexanes as eluent to yield the desired vinylpyridine (690 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 8.40 (1H, s), 7.51 (1H, d, J=8.0 Hz), 7.21 (1H, d, J=8.0 Hz), 6.71 (1H, dd, J=17.5, 10.8 Hz), 6.06 (1H, d, J=17.5 Hz), 5.34 (1H, d, J=10.8 Hz), 4.64 (2H, s), 0.81 (9H, s), 0.00 (6H, s). m/z (ES+) 250 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH:28][CH2:29][CH:30]5[CH2:34][O:33]C(C)(C)[O:31]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1>Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH:28][CH2:29][CH:30]([OH:31])[CH2:34][OH:33])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CC1(C)OCC(CNc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)O1
Agent: Cl
Solvent: C1COCCO1
Product: OCC(O)CNc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-amine (240 mg, 0.52 mmol) was dissolved in dioxane-HCl (20 mL), and then the reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was filtered to gather the solid. Then the solid was washed by DCM (10 mL) to give 450 (130 mg, yield: 53%). 1HNMR (DMSO-d6, 400 MHz): δ8.26 (s, 1H), 7.91-7.85 (m, 1H), 7.70-7.55 (m, 1H), 7.42-7.37 (m, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.99 (s, 1H), 4.15 (t, J=4.4 Hz, 2H), 3.67-3.03 (m, 8H) LC-MS (ESI): m/z=472 [M+H]+
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[C:22]([OH:24])=[O:23])=[O:15])([CH3:12])([CH3:11])[CH3:10].CI>C1COCC1.CCCCCCC.C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1([CH3:2])[C:22]([OH:24])=[O:23])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCCCC1(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of LDA (9.6 mL of a 2M solution in THF/Heptane) in THF (15 mL) at 0° C. was added 1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (2 g as a suspension in 4 mL of THF) dropwise via syringe over 10 minutes. The reaction mixture was stirred a further 20 minutes and then MeI (1.238 g) was added in one portion via syringe. The reaction mixture was allowed to warm to RT and stirred for 72 hours. The reaction was quenched with 2N aqueous HCl solution and diluted with EtOAc. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organics were washed with brine and dried over sodium sulfate. Filtration and evacuation of the volatiles in vacuo afforded a crude residue which was purified by flash column chromatography over silica gel (Heptane/EtOAc) to afford the desired (rac)-2-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (810 mg, MS (ES−): 242.4 (M−H), brown crystals).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: C1CCNC1
Solvent: CCO
Product: CNc1nc(NS(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 63.1 %

Procedure:
0.314 g (0.001 mol) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and 2.5 ml (0.15 mol) of pyrrolidine were stirred in 20 ml of ethanol in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 min. The precipitate was filtered off, dissolved in 150 ml of 1N NaOH and filtered. The filtrate was adjusted to pH 6 with 1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.22 g (63%) of 4-amino-N-(2-methylamino-6-pyrrolidin-1-yl-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: >300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:19][CH2:20][CH2:21][CH2:22][C:23]([C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH:6]=1)=[O:24]
Reactant: COc1cc2ccccc2cc1OC
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2ccc(C(=O)CCCCl)cc2cc1OC

Procedure:
This product was prepared from 2,3-dimethoxynaphthalene (3.76 g), aluminium chloride (2.93 g) and 4-chlorobutanoylchloride (2.96 g) in methylene chloride (100 ml) as described in example 9(a) above.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[S:18][CH:19]=[C:20]([CH3:22])[CH:21]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:21]2[C:20]([CH3:22])=[CH:19][S:18][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=Cc1cc(C)cs1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC(C)=O)c2c(C)csc2c1
Yield: 58.3 %

Procedure:
Sodium acetate (90 g, 1.08 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(4-methylthien-2-yl)but-3-enoic acid (61 g, 0.24 mol) in 700 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 38.5 g (140 mmol, 58%) as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:2][C:3]3[O:4][C:5]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)=[CH:6][C:7]=3[CH2:8][OH:10])[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(Cc3oc(-c4ccc(C(F)(F)F)cc4)cc3CO)CC2)cc1

Procedure:
The title compound was prepared using methyl 2-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 44) and 1-(4-methoxyphenyl)piperazine.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](=[O:22])[CH:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[N+:2]=[N-:3].[C:23](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O.C(OCC)C>[N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([O:22][CH3:23])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: COC1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1
Temperature: 25 °C

Procedure:
Benzyl 6-azido-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (1 mmol) is dissolved in anhydrous acetone (5 ml) and treated with powdered, anhydrous potassium carbonate (2 mmol). The resulting suspension is treated with dimethyl sulfate (1.2 mmol) and stirred vigorously at room temperature for several hours. The mixture is diluted with ethylether and filtered. The filtrate is washed with water and brine, dried and evaporated under vacuum to give benzyl 6-azido-3-methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.