Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:12](=O)[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:12]([N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH3:13]
Reactant: C1=CNc2ccccc2C=C1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1C=CC=Cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
To a solution of the benzazepine (0.98 g, 3.9 mmol) from step E above in dichloromethane (50 mL) were added acetaldehyde (0.44 mL, 7.7 mmol), sodium triacetoxyborohydride (1.8 g, 8.3 mmol), acetic acid (0.2 mL), and 3 Å molecular sieves (1.0 g). The reaction solution was stirred at room temperature for 24 hours and then it was diluted with dichloromethane, washed with aqueous 1N sodium carbonate, dried over sodium sulfate and concentrated in vacuo. The crude product obtained was purified by flash column chromatography (dichloromethane to 95:4.5:0.5 dichloromethane/methanol/concentrated ammonium hydroxide) to give the desired N-ethyl benzazepine (0.53 g, 48%) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.34 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.17 (d, J=7.5 Hz, 2H), 6.75 (d, J=2.5 Hz, 1H), 6.68-6.40 (br, 2H), 4.27 (d, J=8.5 Hz, 1H), 3.94 (d, J=13.5 Hz, 1H), 3.81 (d, J=14.5 Hz, 1H), 3.77 (s, 3H), 3.27-3.16 (br, 1H), 3.06-3.01 (m, 1H), 2.55-2.45 (m, 2H), 2.32-2.24 (m, 1H), 2.13-2.04 (br, 1H), 1.11 (t, J=7.0 Hz, 3H); ESI MS m/z 282 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N+:11]([O-])=O)[C:6](=[O:10])[NH:7][C:8]=1[CH3:9].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO>[NH2:11][C:5]1[C:6](=[O:10])[NH:7][C:8]([CH3:9])=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CSc1cc([N+](=O)[O-])c(=O)[nH]c1C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1cc(N)c(=O)[nH]c1C
Yield: 39162.2 %

Procedure:
To a mixture of 5-methylthio-6-methyl-3-nitropyridin-2(1H)-one (0.60 g, 0.003 mmol) in MeOH (30 mL) at room temperature was added an aqueous solution of sodium hydrosulfite (Na2S2O4) (1.74 g, 0.01 mol). When the yellow color disappeared after addition of additional sodium hydrosulfite (1.7 g), the reaction mixture was extracted with CHCl3 (2×200 mL). The CHCl3 extracts were washed with saturated aqueous NaHCO3 solution, brine and then dried (MgSO4). On concentration under vacuum there was obtained 0.20 g (39.4% yield) of 3-amino-5-methylthio-6-methylpyridin-2(1H)-one as a light yellow solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([C:10](=[O:29])[C:11]1[CH:16]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[F:25])[C:14]([O:26][CH3:27])=[CH:13][C:12]=1[F:28])=[CH:6]N(C)C)[CH3:2].[NH2:31][C@@H:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][OH:34].Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:30])[C:5]([C:10](=[O:29])[C:11]1[CH:16]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[F:25])[C:14]([O:26][CH3:27])=[CH:13][C:12]=1[F:28])=[CH:6][NH:31][C@H:32]([CH2:33][OH:34])[CH:35]([CH3:37])[CH3:36])[CH3:2]
Reactant: CC(C)[C@H](N)CO
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN[C@H](CO)C(C)C)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Temperature: 25 °C

Procedure:
To a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylic acid ethyl ester prepared in Step VIII in toluene was added (S)-2-amino-3-methylbutan-1-ol (3.96 g) with stirring at room temperature. After stirring for 30 min, 1N hydrochloric acid (60 ml) was added, and the mixture was further stirred for 1 hr. The organic layer was separated and washed successively with water (60 ml), 5% sodium hydrogencarbonate (60 ml) and water (60 ml). The organic layer was concentrated under reduced pressure, N,N-dimethylformamide (40 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50 ml) to give a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylic acid ethyl ester in N,N-dimethylformamide. This was identified as the title compound by HPLC.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:17][C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]=1[CH2:27][NH:28][CH3:29]>>[Cl:17][C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]=1[CH2:27][N:28]([CH3:29])[C:14](=[O:16])/[CH:13]=[CH:12]/[C:7]1[CH:8]=[N:9][C:10]2[NH:11][C:2](=[O:1])[CH2:3][CH2:4][C:5]=2[CH:6]=1
Reactant: O=C(O)C=Cc1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1oc2ccccc2c1Cl
Product: CN(Cc1oc2ccccc2c1Cl)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 56 %

Procedure:
According to the method of example 43d, 3-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid (203 mg, 0.8 mmol) and (3-chloro-benzofuran-2-ylmethyl)methylamine (172 mg, 0.88 mmol) were coupled to yield the title compound (176, 56%) as a white solid and as a mixture of amide rotomers. NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.21-7.64 (m, 6H), 4.84-5.08 (rotamers, 2s, 2H), 3.22 (s, 3H), 2.91-2.96 (m, 2H), 2.52-2.59 (m, 2H); MS (ESI) m/e 396 (C21H18ClN3O3+H)+.
Reaction SMILES: [C:1]([C-:3]([C:6]#[N:7])[C:4]#[N:5])#[N:2].[K+].O.[CH2:10]([O:12]CC)[CH3:11].S(=O)(=O)(O)O>C(O)C>[NH2:2][C:1]([O:12][CH2:10][CH3:11])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: CCOCC
Reactant: N#C[C-](C#N)C#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(N)=C(C#N)C#N
Reaction time: 0.33 h

Procedure:
A mixture of 12.9 g of potassium tricyanomethanide from I B, 40 ml of water and 120 ml of diethyl ether was cooled to 5°. To this mixture was added 10 g of concentrated sulfuric acid dropwise at such a rate as to keep the reaction mixture temperature below 10°. Upon complete addition of sulfuric acid, the reaction mixture was stirred during 20 minutes. The mixture was then placed in a separatory funnel and the middle layer drawn off to be used in the next reaction. To 50 ml of the solution from above was added 150 ml of ethanol and volatile material was removed until the boiling temperature exceeded 50°, when the mixture was heated to reflux. The mixture was maintained at the reflux temperature for 15 hours. The white slurry was cooled to 10°, and the solid collected by filtration to give 6.5 g of 3-amino-3-ethoxy-2-cyano-2-propenenitrile, m.p. 233°. A small sample was recrystallized from ethanol without change of melting point. the nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17]([C@@H:19]3[CH2:23][C@@H:22]([F:24])[CH2:21][N:20]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[F:24][C@H:22]1[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C@H:19]([C:17](=[O:18])[NH:16][C@@H:13]2[C@@H:11]3[C@@H:10]([CH2:9][NH:8][CH2:12]3)[CH2:15][CH2:14]2)[CH2:23]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21

Procedure:
To a solution of (2S,4R)-tert-butyl 2-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate (4.59 g, 10.64 mmol) from Step 1 in ethanol (45 mL) was added to 20% Pd(OH)2—C, wet (0.918 g, 6.54 mmol) in a 250 mL stainless steel pressure bottle. The mixture was shaken under 30 psi of hydrogen at 50° C. for 45 minutes. The mixture was filtered through a nylon membrane and the solvent removed in vacuo to give (2S,4R)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate: 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 7.87 (s, 1H), 5.21 (dd, J=53.6, 3.0, 1H), 4.61 (t, J=7.8, 1H), 4.24-4.14 (m, 1H), 3.91 (dd, J=11.6, 3.1, 2H), 3.66 (ddd, J=34.5, 12.8, 3.6, 1H), 3.15-3.05 (m, 2H), 2.96 (dd, J=10.7, 7.3, 1H), 2.68 (dd, J=10.7, 3.7, 1H), 2.64-2.57 (m, 1H), 2.57-2.31 (m, 3H), 2.10-2.00 (m, 1H), 1.95-1.85 (m, 1H), 1.70-1.58 (m, 1H), 1.49 (s, 9H), 1.41-1.30 (m, 1H); MS (ESI+) m/z 342 (M+H)+.
Reaction SMILES: COC1C=C([C:11](=O)[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3CCC[C@H:18]3[CH2:17]2)=O)C=CC=1OC.C(OC(N1CCCC[C@H]1C(O)=O)=O)(C)(C)C.[F:42][C:43]1[CH:44]=[C:45]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[C:46]([CH2:48][CH2:49][C:50]([OH:52])=O)=[O:47]>>[F:42][C:43]1[CH:44]=[C:45]([C:46](=[O:47])[CH2:48][CH2:49][C:50]([N:19]2[CH2:20][CH2:21][N:16]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:17]3[CH2:18]2)=[O:52])[CH:53]=[CH:54][C:55]=1[O:56][CH3:57]
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1F
Agent: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Product: COc1ccc(C(=O)CCC(=O)N2CCN3CCCC[C@H]3C2)cc1F

Procedure:
380 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using (S)-1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline and 3-(3-fluoro-4-methoxybenzoyl)propionic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH2:7][S:6]1)=O.[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][C:3]([C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH2:7][S:6]1)=[O:2]
Reactant: CN
Reactant: COC(=O)[C@@H]1SC[C@@H]2OC(C)(C)O[C@@H]21
Solvent: C1CCOC1
Product: CNC(=O)[C@H]1SC[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 50 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
1.1 g (0.005 mol) of (3aS,4R,6aR)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole-4-carboxylic acid methyl ester compound (7) from the aforementioned Experimental Example 7 were dissolved in 40 mL (0.080 mol) of 2N methylamine solution in tetrahydrofuran, which was stirred at 50° C. for 24 h in a sealed container. After concentration under reduced pressure, the obtained concentrate was purified by silica gel column chromatography using the eluant (hexane:ethyl acetate=2:1) to obtain 953 mg (yield: 87%) of (3aS,4S,6aR)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole-4-carboxylic acid methyl amide as an oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[O:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([NH2:22])([CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>>[OH:9][CH:7]([CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:8][NH:22][C:11]([CH3:21])([CH3:10])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CC(C)(C)OCC1CO1
Product: COc1ccc(CC(C)(C)NCC(O)COC(C)(C)C)cc1
Yield: 34.3 %

Procedure:
Using the method of Example 15, supra, t-butylglycidyl ether (142 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 106 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 310 (M+1, 0.3), 294 (0.5), 222 (1.8), 188 (67.9), 163 (14.6), 132 (100), 121 (19.1); 1H-NMR (CDCl3) δ 7.09 (2H, d, J=8.6), 6.82 (2H, d, JT=8.6), 3.78 (3H, s), 3.68 (1H, m), 3.37 (2H, m), 2.27 (1H, dd, J=11.5 and 4.2), 2.63 (3H, m), 1.19 (9H, s), 1.05 (3H, s), 1.03 (3H, s); 13C-NMR (CDCl3) δ 156.0, 131.3, 130.3, 113.3, 72.9, 69.7, 64.5, 55.1, 52.9, 46.6, 44.7, 27.4, 26.9, 26.8.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=1>C(OCC)C>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:16]=1
Reactant: Fc1cccc(F)n1
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Fc1ccc(-c2cccc(F)n2)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
Butyl lithium (105.0 ml, 0.26 mol, 2.5M solution in hexane) is added to a solution of 1-bromo-4-fluoro benzene (34. 3 ml, 0.31 mol) in anhydrous diethyl ether (200 ml) at -20° C. The mixture is stirred for 60 min and then chilled to -40° C. 2,6-Difluoropyridine (22.7 ml, 0.25 mol) is added and the reaction mixture is allowed to warm to ambient temperature. Subsequently, the mixture is washed with saturated aqueous ammonium chloride (300 ml). The layers are separated and the aqueous layer is washed with diethyl ether 3 times (100 ml each). After drying of the combined organic layers with anhydrous magnesium sulphate, the solvent is removed in vacuo. The crude product is purified by flash column chromatography (silica gel, hexane/AcOEt 8/2) yielding colorless crystals of 2-fluoro-6-(4'-fluorophenyl)-pyridine (19.8 g, 41.0% of th.) with mp 34° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]3[N:17]=[C:18]4[C:24]([C:25](O)=[O:26])=[CH:23][N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:19]4=[N:20][CH:21]=3)=[N:7][N:8]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[C:4]([F:36])[CH:3]=1.F[B-](F)(F)F.[N:42]1(OC(N(C)C)=[N+](C)C)[C:46]2[CH:47]=CC=C[C:45]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>C(#N)C.C(OCC)(=O)C.O>[CH:46]([NH:42][C:25]([C:24]1[C:18]2[C:19](=[N:20][CH:21]=[C:16]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[F:36])[N:8]([CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])[N:7]=3)[N:17]=2)[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:35])[CH3:33])[CH:23]=1)=[O:26])([CH3:47])[CH3:45]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CN(C)CCn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2c(F)cc(Cl)cc21
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN(C)C)c4cc(Cl)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
2-[6-Chloro-1-(2-dimethylamino-ethyl)-4-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (50 mg, 0.094 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (45 mg, 0.14 mmol), N,N-diisopropylethylamine (0.08 ml, 0.47 mmol) and isopropylamine (10 ul, 0.11 mmol) were added together in acetonitrile (1 ml). The reaction was stirred at room temperature for 18 h then 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 sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to give 35 mg (65%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-4-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4](=[O:10])[CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c(=O)cc(Br)c1C
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: Cc1nc(OCc2ccccc2)cc(Br)c1C
Temperature: 25 °C

Procedure:
4-Bromo-5,6-dimethyl-2(1H)-pyridinone (1 eq.), prepared according to the procedure described by McElroy, W. T.; DeShong, P. Organic Letters 2003, 5, 4779-4782, was suspended in benzene (0.13 M). To this was then added silver carbonate (0.6 eq.) and benzyl bromide (1.2 eq.) before the suspension was heated at 45° C. for 3 days in the dark. The reaction suspension was cooled to RT, diluted with benzene and filtered through a bed of celite. The filtrate was washed with sat. aq. NaHCO3, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification by way of column chromatography (SiO2, Hex→10:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([CH:5]1[O:21][C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:8]=2[O:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.C(#N)C>[C:1]([CH:5]1[O:21][C:9]2[N:10]=[C:11]([C:30]3[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:8]=2[O:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1COc2c(nc(Cl)nc2N2CCOCC2)O1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)C1COc2c(nc(-c3cnc(N)nc3)nc2N2CCOCC2)O1
Temperature: 150 °C
Yield: 21.8 %

Procedure:
A microwave vial was charged with 7-tert-butyl-2-chloro-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (50 mg, 0.16 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (70 mg, 0.32 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg, 0.02 mmol, 10 mol %) then sealed. The vessel was evacuated and back filled with nitrogen before the addition of sodium carbonate (0.25 mL, 0.25 mmol, 1M aqueous solution) and acetonitrile (0.75 mL). The mixture was heated at 150° C. for 30 minutes using microwave irradiation before the mixture was filtered and the filtrate concentrated in vacuo. The resultant residue purified by column chromatography (SiO2, 0-5% methanol in DCM) then triturated with cyclohexane/diethyl ether to give 108 as a white solid (13 mg, 22%). LCMS: RT=4.04 min, [M+H]+=373. 1H NMR (400 MHz, CDCl3): δ 9.14 (2H, s), 5.25 (2H, s), 4.44 (1H, dd, J=11.08, 1.92 Hz), 3.99 (1H, dd, J=8.97, 1.89 Hz), 3.91-3.69 (9H, m), 1.12 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[O:15]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C1(C2(CCC3C=CC(C(OC)=O)=C(F)C=3)CC(=O)CC(=O)O2)CCCC1>>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[O:15]2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: COC(=O)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Product: O=C1CC(=O)OC(CCc2ccc(C(=O)O)c(Cl)c2)(C2CCCC2)C1

Procedure:
The title compound was prepared analogously to example B(6): where methyl 2-chloro-4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]benzoate (example B(7)) was substituted in place of methyl 4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorobenzoate in that example. 1H NMR (300 MHz, CDCl3): δ 1.38-2.30 (m, 11 H), 2.78-3.15 (m, 6 H), 7.10 (s, 1 H), 7.19 (d, J=1.58 Hz, 1 H), 7.62 (d, J=1.56 Hz, 1 H) 12.30 (s, 1 H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=2)[C:6](=[O:16])[C:7]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[N:10][C:8]=2[N:9]=1)[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[CH2:1]([S:3][C:4]1[N:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[CH:19][CH:18]=2)[C:6](=[O:16])[C:7]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[N:10][C:8]=2[N:9]=1)[CH3:2]
Reactant: CCSc1nc2nc(CO)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCSc1nc2nc(C=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
2-(Ethylsulfanyl)-7-(hydroxymethyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (373 mg) and triethylamine (6 ml) were dissolved in dimethyl sulfoxide (18 ml), sulfur trioxide pyridine complex (1.16 g) was added thereto by several portions, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (299 mg) as a orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1.[C:30]([N:37]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([N:40]3[CH2:41][CH2:42][CH2:43][N:37]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:38][CH2:39]3)=[CH:7][CH:6]=2)[CH2:9][C:10]([C:20]([C:22]([F:24])([F:23])[F:25])([C:26]([F:28])([F:27])[F:29])[OH:21])=[N:11]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 28.3 %

Procedure:
5-(4-Bromo-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (1.0 g, 1.99 mmol) prepared in Step 4 of Preparation 17, 1-BOC-homopiperazine (589.0 uL, 2.99 mmol), Pd2(dba)3 (91.0 mg, cat.), BINAP (124.0 mg, cat.) and sodium t-butoxide (287.0 mg, 2.99 mmol) were added to toluene (20.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4) to give 350.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:24][NH:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Product: CS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 5-bromo-1H-indole-2,3-dione (Meth-Cohn and Goon, Tetrahedron Letters 1996, 37, 9381-4) and 4-methylsulfonylphenylhydrazine according to Procedure G: 1H NMR (DMSO-d6): δ 12.7 (s, 1H), 11.3 (s, 1H), 7.9 (d, 2H), 7.7-7.8 (m, 3H), 7.4 (dd,1H), 6.9 (d, 1H), 3.2 (s, 3H); ESI−MS m/z 392 (M−H)−.
Reaction SMILES: [K].C([O:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]([CH3:27])([CH3:26])[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][C:11]=1[N:28]1[S:32](=[O:34])(=[O:33])[NH:31][C:30](=[O:35])[CH2:29]1)C1C=CC=CC=1>CCO.O.[Pd]>[CH3:26][C:17]([CH3:27])([C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][C:14]1[CH:13]=[CH:12][C:11]([N:28]2[S:32](=[O:34])(=[O:33])[NH:31][C:30](=[O:35])[CH2:29]2)=[C:10]([OH:9])[CH:15]=1
Reactant: CC(C)(Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)c1ccccc1
Agent: [Pd]
Agent: [K]
Solvent: O
Solvent: CCO
Product: CC(C)(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(=O)c1ccccc1

Procedure:
A solution of 5-[2-benzyloxy-4-(2,2-dimethyl-3-oxo-3-phenylpropyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (60 mg) in 4 mL of EtOH/water (1:1) is hydrogenated over Degussa 5% Pd/C (15 mg) at 1 atm for 30 min. The catalyst is filtered and the solvent is removed under reduced pressure and the residue triturated with ether to give the title compound as a solid: (M−1)−=387. HPLC retention time=1.42 min (Method A).