Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5].[C:10]([O-:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].[K+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:10]([O:15][CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)[O-]
Reactant: CO[Si](CCl)(OC)OC
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=C(C)C(=O)OC[Si](OC)(OC)OC
Temperature: 90 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
170.7 g (1 mol) of chloromethyltrimethoxysilane, 7.9 g (0.03 mol) of triphenylphosphine and 0.1 g (0.05 mol % based on silane) of phenothiazine are placed in a reaction vessel at 90° C. and 130.4 g (1.05 mol) of potassium methacrylate are added a little at a time over a period of 1 hour. After stirring at 90° C. for another 6 hours, the reaction is complete. After filtration from the potassium chloride formed, the product is distilled by means of a short-path evaporator, giving 193.9 g (95%) of methacryloxymethyl-trimethoxysilane having a purity of 98.4%.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[CH3:34][C:35](=O)[CH3:36]>CO.[Pd]>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH:35]([CH3:36])[CH3:34])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Reactant: CC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (553 mg, 1.23 mmol) and propan-2-one (1.0 mL) in MeOH (20 mL) was added 10% Pd/C (30 mg) as a slurry in MeOH (0.5 mL) and the resulting mixture stirred under an atmosphere of H2 for 1.5 h at r.t. The reaction mixture was filtered through Celite®, washing with MeOH, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, 2M NH3/MeOH:EtOAc, 0-12%) then (C18, MeOH:H2O, 5-25%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH. The resulting colourless foam was recrystallised from iPrOAc and pentane affording 739 as colourless crystals (166 mg, 28%). LCMS (method I): RT 2.48 min, [M+H]+ 491.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-8.02 (1 H, m), 7.64-7.63 (1 H, m), 7.29-7.28 (2 H, m), 4.40 (4 H, s), 4.05 (2 H, d, J=8.89 Hz), 3.86 (4 H, s), 3.81 (3 H, s), 3.57-3.55 (2 H, m), 3.31-3.30 (2 H, m), 3.10 (3 H, s), 2.54-2.53 (1 H, m), 1.40 (3 H, t, J=7.50 Hz), 1.02 (6 H, d, J=6.24 Hz)
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:18])[C@H:13]([CH:15]([CH3:17])[CH3:16])[NH2:14])[CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:31]2[CH:30]([C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>>[CH:28]1[C:29]2[CH:30]([C:32]([NH:34][CH2:35][C:36]([NH:14][C@H:13]([C:12]([NH:11][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=3[C:8]([OH:10])=[O:9])=[O:18])[CH:15]([CH3:16])[CH3:17])=[O:37])=[O:33])[C:31]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)CNC(=O)C1c2ccccc2-c2ccccc21
Reactant: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Product: Cc1cccc(NC(=O)[C@@H](NC(=O)CNC(=O)C2c3ccccc3-c3ccccc32)C(C)C)c1C(=O)O
Yield: 33.4 %

Procedure:
84 mg of 2-[[[N-(9-fluorenylcarbonyl)glycyl]-L-valyl]amino]-6-methylbenzoic acid was prepared exactly as in step c) of Example 3, except that 126 mg of 6-methyl-2-(L-valylamino)benzoic acid was subjected to a condensation reaction with 188 mg of N-(9-fluorenylcarbonyl)glycine in place of 9-fluorenyloxyacetic acid used in Example 3.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:28](=[C:29]([C:39](O)=[O:40])[CH:30]=[C:31]([Cl:38])[CH:32]=4)[NH:27]3)[CH:21]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:28](=[C:29]([C:39]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:40])[CH:30]=[C:31]([Cl:38])[CH:32]=4)[NH:27]3)[CH:21]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)NS(=O)(=O)C4CC4)CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a suspension of 60% sodium hydride (128 mg, 3.2 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (400 mg, 3.3 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 0.33 mmol)) and 1,1′-carbonyldiimidazole (136 mg, 0.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (72 mg, 40%) as a white solid: LC/MS m/e calcd for C31 H35ClN2O3S (M+H)+: 552.11, observed: 551.1.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[CH:27]([CH2:28][CH:29]=O)[C:26]2[C:17](=[CH:18][C:19]([CH2:31][C:32]3[CH:33]=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=3)=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[C:16]1=[O:39])(C(C)(C)C)(C)C.[CH3:40][NH:41][CH3:42].C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl>[Cl:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][C:19]2[CH:18]=[C:17]3[C:16](=[O:39])[N:15]([C@H:10]4[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]4[OH:8])[CH:27]([CH2:28][CH2:29][N:41]([CH3:42])[CH3:40])[C:26]3=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[N:24]3)=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCCC[C@@H]1N1C(=O)c2cc(Cc3ccc(Cl)nc3)c3cccnc3c2C1CC=O
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)CCC1c2c(cc(Cc3ccc(Cl)nc3)c3cccnc23)C(=O)N1[C@H]1CCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of {8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-chloropyridin-3-yl)methyl]-7-oxo-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-9-yl}acetaldehyde (see Example 22, 0.033 g, 0.058 mmol) in 1.2 mL of 1,2-dichloroethane was added dimethylamine (2 M in tetrahydrofuran, 0.059 mL, 0.12 mmol), acetic acid (0.0034 mL, 0.058 mmol), sodium cyanoborohydride (3.7 mg, 0.058 mmol), and 4 Å molecular sieves. The mixture was irradiated in a microwave reactor at 100° C. for 20 min, cooled to ambient temperature, and filtered. The filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 2 mL of dichloromethane and treated with hydrochloric acid (6 M aqueous, 4 drops). After 14 hr, the mixture was diluted with dichloromethane, washed 2× with saturated aqueous sodium bicarbonate, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 479.2200 for [M+H]+ [calc'd for C27H32CN4O2, [M+H]+=479.2208]: 1H NMR (400 MHz, CDCl3) δ 8.97-8.96 (m, 1H), 8.34-8.28 (m, 2H), 7.78 (s, 1H), 7.54-7.50 (m, 1H), 7.44-7.40 (m, 1H), 7.24 (d, J=8.3 Hz, 1H), 5.21-5.19 (m, 1H), 4.69-4.51 (m, 1H), 4.47 (s, 2H), 3.42-3.33 (m, 1H), 3.29-3.15 (m, 2H), 2.76-2.63 (m, 1H), 2.49 (s, 6H), 2.29-2.17 (m, 2H), 1.81-1.68 (m, 2H), 1.48-1.00 (m, 5H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:15])=[N:10][CH:11]=[C:12](Br)[N:13]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:25]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2nc(Br)cnc2N)cc1
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2nc(-c3ccnc(N4CCOCC4)c3)cnc2N)cc1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
A suspension of the compound prepared in Example 12 (7.6 g), Pd(PPh3)4 (3.3 g), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (8.3 g), and Na2CO3 (9.1 g, 85 mmol) in a 3 to 1 mixture of dioxane/water (280 mL) was degassed with a stream of nitrogen for 10 minutes. The reaction was heated at 90° C. overnight, at which time LC/MS indicated the reaction was complete. The mixture was concentrated, diluted with aqueous saturated sodium bicarbonate solution (200 mL) and extracted with EtOAc (3×200 mL). The organic layers were combined, dried over Na2SO4, and evaporated under reduced pressure. The crude product was obtained as a brown oil which was precipitated from DCM (50 mL) to give a dark yellow solid. The solid was filtered and triturated with a 1 to 1 solution of DCM/EtOAc (3×50 mL) to give the title compound (8.4 g) having the following physical data as a light yellow solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.CON(C)[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[O:25])=[CH:8][CH:9]=1
Reactant: CON(C)C(=O)c1ccc(C)cc1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (8.20 g) in THF (dry) (75 mL) was added TEA (23.4 mL) at 0° C. After being stirred at 0° C. for 20 min, 4-methylbenzoyl chloride (10 g) in THF (dry) (20 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 2 days. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give N-methoxy-N,4-dimethylbenzamide (11.7 g) as a yellow oil. n-Butyllithium (1.6 M in hexane) (25.1 mL) was added dropwise to a mixture of 1,4-dibromobenzene (8.29 g) in THF (dry) (105 mL) at −78° C. for 10 min. The mixture was stirred at the same temperature under nitrogen for 30 min to form white precipitates. A solution of N-methoxy-N,4-dimethylbenzamide (6 g) in THF (dry) (20 mL) was added to the reaction mixture at −78° C. and the mixture was stirred at the same temperature under nitrogen for 30 min and then at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with sat. NH4Cl aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (7.18 g) as a pale yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[CH:11]=[O:12].[BH4-].[Na+]>CCO>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[CH2:11][OH:12]
Reactant: O=Cc1cc2c(cc1I)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc2c(cc1I)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To a solution of 6-iodoindane-5-carbaldehyde (35.5 mg, 0.131 mmol) in EtOH anhydrous (3 mL) under N2 at 0° C., was added NaBH4 (20 mg, 0.522 mmol) as a powder. The mixture was warmed to room temperature and stirred for 0.5 h. The mixture was quenched with water. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford (6-iodo-2,3-dihydro-1H-inden-5-yl)methanol (36.3 mg, 100%). 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 7.33 (s, 1H), 4.68 (d, J=6.3 Hz, 2H), 2.92-2.88 (m, 4H), 2.12-2.06 (m, 2H), 1.96 (t, J=6.4 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][NH2:27])[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:26][NH:27][C:14]([C:10]1[S:9][C:8]([N:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]2=[O:17])=[N:12][C:11]=1[CH3:13])=[O:16]
Reactant: NCc1ccc(F)c(F)c1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 88 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with (3,4-difluorophenyl)methanamine, the title compound was obtained as a colorless solid in 88% yield: mp 294-296° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.50 (br s, 1H), 8.77 (t, J=5.8 Hz, 1H), 8.59 (d, J=8.0 Hz, 1H), 7.40-7.28 (m, 2H), 7.15-7.10 (m, 1H), 6.26 (dd, J=8.0, 2.6 Hz, 1H), 5.82 (d, J=2.6 Hz, 1H), 4.35 (d, J=5.8 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 162.1, 161.6, 154.2, 150.5, 137.7, 132.6, 124.5, 123.3, 117.8, 117.6, 116.8, 116.6, 104.4, 98.0, 42.2, 17.5; MS (ES+) m/z 378.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].Cl[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=O)[C:17](=O)N2>>[C:15]1([CH:16]([C:17]2[CH:4]=[CH:3][CH:2]=[CH:10][CH:6]=2)[N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:12])[C:8]2=[O:11])[CH:19]=[CH:20][CH:21]=[CH:22][CH:14]=1
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(F)cccc21

Procedure:
Following the procedure as described in PREPARATION 4A, and making non-critical variations using 7-fluoro-1H-indole-2,3-dione (Kalia, N., et al., J. Med. Chem. 2007; 50:21-39) to replace 4-chloro-1H-indole-2,3-dione, 1-(diphenylmethyl)-7-fluoro-1H-indole-2,3-dione was obtained (56%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ7.52-7.47 (m, 1H), 7.42-7.30 (m, 10H), 7.29-7.21 (m, 1H), 7.13-7.05 (m, 1H), 6.99 (br s, 1H); MS (ES+) m/z 353.9 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[C:8]3[CH2:29][S:28][CH2:27][CH2:26][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[CH:23][N:22]=[C:21]4[CH3:25])=[CH:16][CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]3[CH2:29][S:28](=[O:40])[CH2:27][CH2:26][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[CH:23][N:22]=[C:21]4[CH3:25])=[CH:18][CH:19]=3)[N:12]=2)=[CH:30][CH:31]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CSCC3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CS(=O)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
4-(4-Fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (103 mg, 0.24 mmol) was dissolved in DCM (3 mL). mCPBA (61.8 mg, 0.36 mmol) was added and the reaction was stirred at rt for 2 h. Water was added and the product was obtained by separating the organic phase and evaporating the solvent. The crude product was purified using preparative HPLC yielding 4-(4-fluorobenzyl)-N-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine 6-oxide (21.0 mg, 18.9%). MS (ES+) m/z 448.1 (M+H)+
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+]>C(O)(=O)C>[CH2:16]([O:20][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1)[C:17]#[C:18][CH3:19]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC#CCOc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To 70 ml of N,N-dimethylformamide, 3.00 g (19 mmol) of 6-chloronicotinic acid and 2.00 g (29 mmol) of 2-butyne-1-ol were dissolved, followed by adding 1.80 g (45 mmol) of 60% sodium hydride, stirring at room temperature for 1 hour and stirring at 140° C. for 3 hours. The reaction liquid was then poured in 150 ml of ice water, and acetic acid was added to make pH 5, followed by adding 50 ml of a saturated saline solution. The crystal precipitated was filtered, washed with cold water and hexane and dried to obtain 0.96 g (yield: 26%) of 6-(2-butynyloxy)nicotinic acid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N+:9]([O-])=[CH:10]2)=[CH:5][CH:4]=1.BrC1C=C2C(=CC=1)C([Cl:25])=NC=C2>>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[Cl:25])=[CH:5][CH:4]=1
Reactant: Clc1nccc2cc(Br)ccc12
Reactant: [O-][n+]1ccc2ccc(Br)cc2c1
Agent: Cl
Product: Clc1nccc2ccc(Br)cc12

Procedure:
Compound 37b was prepared from 37a using the procedure described for 1b. 1H-NMR 200 MHz (CDCl3) δ: 7.57-7.88 (3H, m), 8.32 (1H, d, J=6 Hz), 8.51-8.54 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([CH2:24][CH2:25][CH3:26])[C:21](=[O:23])[CH3:22].[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([CH2:24][CH2:25][CH3:26])[C:21]1([O:29][CH2:28][CH2:27][O:23]1)[CH3:22]
Reactant: OCCO
Reactant: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C1(C)OCCO1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 1.5 g. of N-[4-bromo-3(1-propyl-2-oxopropoxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 0.7 g. of ethyleneglycol, 0.1 g. of p-toluenesulfonic acid and 30 ml. of benzene was refluxed with stirring under removing water for 5.5 hours and the reaction mixture was cooled to room temperature and 0.4 ml. of triethylamine was added. The solvent was distilled off under a reduced pressure. The residue was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane:triethylamine of 30:80:1) to obtain 1.2 g. of Compound No. 49 shown in Table 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1)(=[O:30])=[O:29]>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:6]1[CH:7]=[C:2]([C:33]2[CH:34]=[N:35][CH:36]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:32]=2)[CH:3]=[CH:4][C:5]=1[F:26])[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: Cc1cc(C2(c3cc(Br)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Product: Cc1cc(C2(c3cc(-c4cncc(S(C)(=O)=O)c4)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Yield: 32 %

Procedure:
The title compound was synthesized as described for Example 1 in 32% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine (80 mg, 0.19 mmol) and 5-(methylsulfonyl)pyridin-3-ylboronic acid (50.5 mg, 0.25 mmol). 1H NMR (500 MHz, DMSO-d6, 298 K) δ ppm 9.07 (d, 1 H), 9.04 (d, 1 H), 8.39 (t, 1 H), 8.31 (d, 1 H), 7.84 (m, 1 H), 7.62-7.69 (m, 2 H), 7.56 (m, 1 H), 7.38 (dd, 1 H), 7.28-7.34 (m, 1 H), 7.04 (s, 1 H), 6.98 (dd, 1 H), 6.76 (br. s., 2 H), 3.37 (s, 3 H), 2.38 (s, 3 H); MS (ES+) m/z 491 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:7])[NH:5][NH2:6])[CH3:2].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O>>[CH2:1]([NH:3][C:4](=[S:7])[NH:5][N:6]=[CH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)[CH3:2]
Reactant: O=Cc1ccccn1
Reactant: CCNC(=S)NN
Product: CCNC(=S)NN=Cc1ccccn1

Procedure:
The title compound was prepared from 4-ethyl-3-thiosemicarbazide (100 mg, 0.838 mmol) and 2-pyridinecarboxaldehyde (80 μL, 0.838 mmol) similar to Example 3 and isolated as a white solid (137 mg, 78%). 1H NMR (DMSO-d6): 11.65 (s, 1H), 8.72 (t, J=5.4 Hz, 1H), 8.58-8.55 (m, 1H), 8.27 (dd, J=1.1, 8.1 Hz, 1H), 8.09 (s, 1H), 7.88-7.82 (m, 1H), 7.40-7.36 (m, 1H), 3.65-3.56 (m, 2H), 1.16 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:28])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][CH:29]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(OCC(=O)OCCOC(=O)COc2ccc(N)cc2)cc1
Yield: 75.8 %

Procedure:
(4-Nitrophenoxy)-acetic acid-2-[2-(4-nitrophenoxy)-acetoxy]-ethyl ester 24 (100 g, 238 mmol) was dissolved in dry dimethyl formamide (500 ml) in a pressure vessel, palladium on carbon (5%, 22 g) was added, and the mixture stirred under an atom-sphere of hydrogen (4 kg) for 6 hours. The catalyst was removed by filtration and ice water (2.5 L) was added to the filtrate. Crude 25 was filtered off, dried and recrystal-lised in a mixture of methanol:chloroform (1:1) to give pure 25 (65 g, 78%) as a light brown shining powder with an m.p. between 124-125.8° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][N:4]=1.[CH3:12][O:13][N:14]=[C:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=O)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>>[CH3:12][O:13][N:14]=[C:15]1[C:23]2[C:18](=[CH:19][C:20](/[CH:24]=[CH:10]/[C:9]([C:6]3[CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=3)=[O:11])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CSc1ncc(C(C)=O)cn1
Reactant: CON=C1CCc2cc(C=O)ccc21
Product: CON=C1CCc2cc(/C=C/C(=O)c3cnc(SC)nc3)ccc21
Yield: 28 %

Procedure:
The title compound (2.6 g, 28%) was prepared from the product of Step 1 and the product of Example 1 Step 2 using the method of Example 2 Step 1; MS(ES+) m/e 340 [M+H]+.