Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl.O>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[N:13]=[CH:12][C:11]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ccc(-c2[nH]ncc2-c2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc(-c2ccncc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
55% Sodium hydride (1.41 g, 32.1 mmol) was suspended in tetrahydrofuran (300 ml). To the suspension was added 5-(4-chlorophenyl)-4-(pyridin-4-yl)pyrazole (8.21 g, 32.1 mmol), and the resulting mixture was stirred at room temperature for 1 hour. To the resulting mixture was added (2-trimethylsilylethoxy)methyl chloride (5.68 ml, 32.1 mmol) dropwise under ice cooling, and the mixture was stirred at room temperature overnight. At the end of this time, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=3:1), to give the title compound (11.12 g) as a pale brown oil (yield 90%).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH:22]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][N:9]1[C:28]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:29])=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1
Reactant: O=C(O)C1CCCCC1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=O)C1CCCCC1

Procedure:
L2. (2S,4R)-4-Benzenesulfonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride prepared in analogy to experiment K1 was coupled with cyclohexanecarboxylic acid in analogy to experiment A1 to give (2S,4R)-4-benzenesulfonyl-1-cyclohexanecarbonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a white solid. MS: 404.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH:26]([CH3:27])[CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[CH:26]([CH3:27])[CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1CCNC(=O)CC1N
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CC1CCNC(=O)CC1NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure B above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino4-methyl-ε-caprolactam (General Procedure—C), the title compound was prepared as a mixture of diasteromers. The reaction was monitored by tlc on silica gel (Rf=0.18 in 5% MeOH/dichloromethan).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7](=[O:9])[CH3:8])[CH2:2]1.C(N(CC)CC)C.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:7]([CH:3]1[O:4][CH2:5][CH2:6][N:1]([C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:2]1)(=[O:9])[CH3:8]
Reactant: CC(=O)C1CNCCO1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)C1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a solution of 1-(morpholin-2-yl)ethanone (3.9 g, 30.0 mmol) in DCM (60 mL) was added triethylamine (1.0 g, 10 mmol) to adjust pH 9. Then benzyl carbonochloridate (5.6 g, 33.0 mmol) and triethylamine (3.0 g, 30.0 mmol) were added and the mixture was stirred at room temperature for 16 hr. The reaction solution was added 1120 (20 mL) and extracted by DCM (100 mL*3). The organic layer was concentrated and purified by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=20/1-15/1-10/1) to give benzyl 2-acetylmorpholine-4-carboxylate (5.0 g, 63%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N:13]([CH2:18][CH3:19])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][N:10]2[N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]([C:23](=[O:26])[NH:24][CH3:25])=[C:9]2[CH:8]=1)(=O)=O.[CH3:36][C:37]1[CH:54]=[CH:53][C:40]([C:41]([NH:43][C:44]2([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH2:46][CH2:45]2)=[O:42])=[CH:39][C:38]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:18]([N:13]([C:12]1[C:7]([C:38]2[CH:39]=[C:40]([C:41](=[O:42])[NH:43][C:44]3([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=4)[CH2:45][CH2:46]3)[CH:53]=[CH:54][C:37]=2[CH3:36])=[CH:8][C:9]2[N:10]([N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]=2[C:23]([NH:24][CH3:25])=[O:26])[CH:11]=1)[S:14]([CH3:17])(=[O:15])=[O:16])[CH3:19]
Reactant: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OS(=O)(=O)C(F)(F)F)S(C)(=O)=O
Reactant: Cc1ccc(C(=O)NC2(c3ccccn3)CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cc(C(=O)NC2(c3ccccn3)CC2)ccc1C)S(C)(=O)=O
Temperature: 90 °C

Procedure:
6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (0.07 g, 0.13 mmol, 1 eq), 4-methyl-N-(1-(pyridin-2-yl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.054 g, 0.14 mmol, 1.1 eq), tetrakistriphenylphosphine palladium (0.0045 g, 0.0039 mmol, 0.03 eq) and cesium carbonate (0.12 g, 0.39 mmol, 3 eq) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). Nitrogen gas was passed through the solution and the reaction was heated at 90° C. for 14 h. The solution was filtered through celite. Water was added to the filtrate which was then extracted with ethyl acetate. The organic layer was concentrated and the residue obtained purified by Preparative HPLC. Yield: 22 mg (26%). 1HNMR (400 MHz, CD3OD): δ 1.12 (broad s, 3H), 1.35 (s, 2H), 1.66 (s, 2H), 2.34 (s, 3H), 2.85 (s, 3H), 3.00-3.32 (br, 3H), 3.51 (br, 2H), 7.13 (m, 1H), 7.24 (m, 2H), 7.46 (m, 2H), 7.68 (m, 1H), 7.97 (m, 4H), 8.0 (s, 1H), 8.41-8.42 (d, J=4 Hz, 1H), 8.92 (s, 1H). LCMS: (ES+) m/z=641.2 (M+H) Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm); Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH; Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min; RT min: 1.796; Wavelength: 220 nm. HPLC Method: SUNFIRE C18 (4.6×150) mm, 3.5 micron; Buffer: 0.05% TFA in water pH 2.5; Mobile Phase A: Buffer: MeCN (95:5); Mobile Phase B: MeCN: Buffer (95:5); FLOW: 1 ml/min; Wavelength: 254 nm, RT min: 8.675; Purity: 96.6%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13].Cl[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]([C:3]1[CH:4]=[C:5]([C:8]2[S:10][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:9]=2)[CH:6]=[CH:7][C:2]=1[OH:1])[CH2:12][CH3:13]
Reactant: O=C1CCCCC1Cl
Reactant: CCCc1cc(C(N)=S)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1O
Yield: 96.9 %

Procedure:
A suspension of 4-hydroxy-3-propyl-thiobenzamide (5 g, 0.026 mol) (Example 34), 2-chlorocyclohexanone (4.07 g, 0.031 mol), and p-toluenesulfonic acid monohydrate (0.244 g, 1.28 mmol) in anhydrous toluene (100 mL) was heated to reflux in a Dean-Stark apparatus under argon for 12 h. At about 90° C., the mixture became a red orange oil and after 4 h of refluxing, precipitation was observed. The reaction mixture was cooled and diluted with ethyl acetate (50 mL). The organic layer was washed successively with saturated sodium bicarbonate (2×50 mL), water (2×50 mL), brine, dried over sodium sulfate, and concentrated to give the desired product as a tan solid (6.89 g, 98%). LC/MS m/z 274.3 (M+H)+, RT 2.99 min. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.53-7.44 (m, 2H), 6.81 (d, 1H), 2.72-2.68 (m, 4H), 2.54-2.49 (m, 2H), 1.78 (b, 4H), 1.58-1.53 (m, 2H), 0.90 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>O1CCOCC1>[CH3:33][N:34]([CH3:38])[C:35]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)=[O:23])[CH2:15][CH2:14]1)=[O:36]
Reactant: CN(C)C(=O)Cl
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea (0.8 mmol), prepared as described in general procedure (G), steps 1-3, and 1.2 equivalents of DIPEA in 10 mL dioxane was added dimethylcarbamoyl chloride (1.2 equivalents) in 1 ml dioxane. The reaction was stirred overnight at room temperature, concentrated in vacuo and purified by flash chromtography to give the title compound.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26]C(C)(C)[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cu](C#N)[C:32]#[N:33].CC(N(C)C)=O>O>[OH:24][C@H:23]([CH2:27][OH:26])[CH2:22][O:21][C:19]1[CH:18]=[CH:17][C:9]2[C:10]([CH3:15])([CH3:16])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[C:7](=[O:30])[C:8]=2[CH:20]=1)=[CH:4][CH:3]=[C:2]([C:32]#[N:33])[CH:14]=4
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1(C)c2ccc(OC[C@H](O)CO)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Yield: 21.5 %

Procedure:
3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 49.5 mg, 0.105 mmol) and copper cyanide (90%, 35.3 mg, 3.4 eq.) were added with DMA (0.5 mL), and the mixture was irradiated with microwave at 200° C. for 1 hr under nitrogen atmosphere. After cooling, the reaction solution was added with water and extracted with ethyl acetate. The insoluble matters were separated off by filtration, and the organic layer was washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting residues were purified by preparative TLC (methanol/dichloromethane) to obtain the title compound (white solid, 8.5 mg, 22%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[N:3]=1.[CH3:22][O:23]C1C=CC(NN)=CC=1>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][C:18]([O:23][CH3:22])=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[N:3]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Product: COc1ccc(-n2nc3c4nc(F)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described in Step 3 for synthesis for 5a using 4-methoxyphenylhydrazine instead of phenylhydrazine. 1H-NMR (DMSO-d6) δ (ppm): 7.25 (1H, ddd, J=7.14, 4.67, 1.10 Hz), 7.50 (1H, dd, J=8.79, 3.03 Hz), 7.90 (1H, ddd, J=9.34, 7.42, 1.93 Hz), 8.14 (1H, brd, J=8.24 Hz), 8.28 (1H, ddd, J=9.06, 7.42, 7.14 Hz), 8.50 (1H, m), 8.84 (1H, s). m/z 282.3 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(OCc4cccc(F)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (53 mg, 0.30 mmol) was reacted with 4-[2-amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol (102 mg, 0.30 mmol) for 20 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (60 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3H) 5.16 (s, 2H) 6.27 (d, J=6.99 Hz, 1H) 6.64 (d, J=8.46 Hz, 2H) 7.03-7.36 (m, 7H) 7.45 (m, J=6.26 Hz, 1H) 7.80 (d, J=8.82 Hz, 1H) 8.39 (d, J=6.98 Hz, 1H) 8.99 (d, J=8.82 Hz, 1H) 9.78 (s, 1H) 11.02 (br s, 1H) 14.39 (br s, 1H); MS (ESI+) m/z, 484 (M+H−TFA)+; (ESI−) m/z, 482 (M−H−TFA)−.
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16].O=P(Cl)(Cl)Cl>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(C(F)(F)F)cc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(C(F)(F)F)cc1Cl
Temperature: 80 °C

Procedure:
The crude 5-nitro-2-trifluoromethyl-pyridin-4-ol (3.4 g, 16.3 mmol) was treated with PCl5 (5.2 g, 24.97 mmol) and POCl3 (7 mL, 24.49 mmol). The resulting mixture is heated at 80° C. for 18 h, cooled and poured into ice-cold water, and extracted with CH2Cl2. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 4-Chloro-5-nitro-2-trifluoromethyl-pyridine as an yellow oil. 1H NMR (300 MHz, CDCl3): δ 9.17 (s, 1H) 7.9 (s, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[CH3:35][O:36][C:37]1C=C(C=[CH:43][CH:44]=1)C=O>>[CH3:35][O:36][C:37]1[CH:9]=[C:8]([CH:13]=[CH:43][CH:44]=1)[CH2:7][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: COc1cccc(C=O)c1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)c1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 3-methoxybenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.27-7.21 (m, 1H), 6.96-6.92 (m, 2H), 6.81 (d, J=7.1 Hz, 1H), 4.82-4.76 (m, 1H), 4.14-4.08 (m, 2H), 3.85 (s, 3H), 3.79 (s, 1H), 3.62-3.54 (m, 3H), 3.39 (t, J=8.7 Hz, 1H), 3.00 (d, J=10.3 Hz, 1H), 2.81 (m, 1H), 2.53 (m, 1H), 2.42-2.28 (m, 3H), 1.94-1.82 (m, 3H), 1.20 (d, J=7.1 Hz, 3H). MS: (M+H m/z 424.1).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[S:12].C[Si](C)(C)Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH4+].[OH-]>N1C=CC=CC=1.CO>[C:23]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:3]2[O:4][C@H:5]([CH2:8][OH:9])[C@@H:6]([OH:7])[C@H:2]2[CH3:1])[C:11](=[S:12])[N:13]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=S
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=S
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
To a stirred solution of 2'-deoxy-2'-methylthiocytidine (0.86 g, 3.15 mmol) in dry pyridine (20 ml) was added trimethylchlorosilane (2.0 ml, 15.75 mmol), and stirring continued for 15 min. Benzoyl chloride (2.18 ml, 18.9 mmol) was added to the solution followed by stirring for 2 hr. The mixture was then cooled in an ice-bath and MeOH (10 ml) was added. After 5 mins., NH4OH (20 ml, 30% aq.) was added and the mixture stirred for 30 min. The reaction mixture was then concentrated under vacuum and the residue purified by short silica gel (70 g) column chromatography. Elution with CH2Cl2 :MeOH (9:1, v/v), pooling of appropriate fractions and evaporation furnished the title compound (0.55 g, 46.6%) which crystallized from EtOH as needles, m.p. 193°-194° C.
Reaction SMILES: [O:1]=[C:2]([NH:13][CH2:14][C:15]1[NH:16][C:17](=[O:25])[C:18]2[CH2:24][O:23][CH2:22][CH2:21][C:19]=2[N:20]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1.[Cl:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[Cl:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][N:31]([C:10]([CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][C:2]([NH:13][CH2:14][C:15]3[NH:16][C:17](=[O:25])[C:18]4[CH2:24][O:23][CH2:22][CH2:21][C:19]=4[N:20]=3)=[O:1])[CH2:5][CH2:6]1)=[O:12])[CH2:32]2
Reactant: Clc1cccc2c1CCNC2
Reactant: O=C(CN1CCC(C(=O)O)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Product: O=C(CN1CCC(C(=O)N2CCc3c(Cl)cccc3C2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Yield: 17.6 %

Procedure:
The title compound (44 mg, 18% yield) was prepared following the general procedure of Example 1 from 1-(2-oxo-2-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylamino)ethyl)piperidine-4-carboxylic acid (250 mg, 0.50 mmol) and 5-chloro-1,2,3,4-tetrahydroisoquinoline (84 mg, 0.50 mmol). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (br. s., 1H), 7.32 (d, J=6.6 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 4.74 (br. s., 1H), 4.64 (s, 1H), 4.34 (s, 2H), 4.18 (d, J=5.6 Hz, 2H), 3.66-3.87 (m, 4H), 3.09-3.20 (m, 1H), 2.95 (s, 4H), 2.79-2.91 (m, 2H), 2.73 (br. s., 1H), 2.67 (br. s., 1H), 2.02-2.23 (m, 2H), 1.74 (br. s., 4H). HRMS calculated for C25H30ClN5O4 500.2065. found (ESI, [M+H]+), 500.2066. Retention time=1.36 min.
Reaction SMILES: [S:1]1[C:5]([C:6]2([OH:19])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.C[O:25][C:26](=[O:49])[C@H:27]([C@@H:46]([CH3:48])O)[NH:28]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[S:1]1[C:5]([C:6]2([O:19][C@H:46]([CH3:48])[C@@H:27]([C:26]([OH:49])=[O:25])[NH2:28])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: OC1(c2cc3ccccc3s2)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OC1(c2cc3ccccc3s2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(benzo[b]thien-2-yl)-9H-fluoren-9-ol (Example 2n) and UW-(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(Cl)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Chlorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.23 (t, 1H), 7.19 (s, 1H), 6.90 (d, 1H), 6.79 (d, 1H), 5.37 (s, 2H), 3.58 (m, 4H), 3.29 (m, 2H), 3.19 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=421.1, found=421.0.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:24]([N:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([N:26]([CH2:30][CH3:31])[C:27]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)=[O:23])[CH2:15][CH2:14]1)=[O:28])[CH3:25]
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and diethylcarbamoyl chloride
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:54]=[CH:53][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=4[F:52])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:52][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]([F:51])[C:45]=1[CH2:44][NH:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:33]2[CH:53]=[CH:54][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=3)=[CH:31][CH:32]=2)[CH2:36][CH2:37]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4c(F)cccc4F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1c(F)cccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 62.5 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(2,6-difluorobenzyl)-1-piperidinecarboxamide (0.192 g, 0.24 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.085 g, 0.15 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl-].[CH3:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[CH:15]=[N+:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:15]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:14]1[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=1[CH3:12])=[CH:5][NH:6]2
Reactant: Cc1cccc2[nH]ccc12
Reactant: Cc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: Cc1ccccc1C(c1c[nH]c2cccc(C)c12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-methyl-1H-indole and 1-(2-methyl-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 30.