Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]=[CH:6][N:5]([C@@H:8]2[O:20][C@H:19]([CH2:21][O:22]C(=O)C)[C@@H:14]([O:15]C(=O)C)[C@H:9]2[O:10]C(=O)C)[N:4]=1)#[N:2].[OH:26]O>N>[C@@H:8]1([N:5]2[CH:6]=[N:7][C:3]([C:1]([NH2:2])=[O:26])=[N:4]2)[O:20][C@H:19]([CH2:21][OH:22])[C@@H:14]([OH:15])[C@H:9]1[OH:10]
Reactant: OO
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 6 h
Yield: 51.2 %

Procedure:
A mixture of 3-cyano-1-(2,3,5 -tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazole (705 mg., 2.0 mmole), 28% aqueous ammonia (20 ml.) and 30% hydrogen peroxide (3.0 ml.) was stirred at 25° for 6 hrs. An additional 3.0 ml. portion of 30% hydrogen peroxide was then added and stirring at 25° was continued for 12 hrs. The excess hydrogen peroxide was destroyed by addition of platinum black, the solution was filtered, the filtrate was evaporated to dryness. The residue was dissolved in methanol and silic gel (5.0 g.) was added to the solution. The solvent was removed and the silica gel mixture was applied to a silica gel column. Elution with ethyl acetate-methanol (1:1) provided 1-(β -D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (250 mg., 51.2%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][C:18]([OH:20])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:21]([C@H:24]1[C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][C:26](=[S:41])[NH:25]1)([CH3:23])[CH3:22].P([O-])(O)(O)=O.[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][C:18]([N:25]1[C@@H:24]([CH:21]([CH3:23])[CH3:22])[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:27][C:26]1=[S:41])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(C)[C@@H]1NC(=S)OC1(c1ccccc1)c1ccccc1
Reactant: CCCCCCCOCCCCCC/C=C/CC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCOCCCCCC/C=C/CC(=O)N1C(=S)OC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, (E)-10-heptyloxy-dec-3-enoic acid obtained in Step C-3 (209.7 mg, 0.698 mmol) and a commercially available reagent of (S)-4-isopropyl-5,5-diphenyl-oxazolidine-2-thione (207.5 mg, 0.698 mmol) were dissolved in dichloromethane (3.13 mL), and the mixture was cooled to 0° C. While maintaining the temperature at 0° C., N,N-dimethyl-4-aminopyridine (8.5 mg, 0.0698 mmol) and WSCl (173.9 mg, 0.907 mmol) were added in order. The mixture was stirred at 0° C. for 2.0 minutes and at room temperature for 16 hours. To the reaction solution was added an aqueous solution (4.2 mL) of 10% sodium dihydrogen phosphate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine in order, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The resulting residue was then purified with SP1 (SiO2 cartridge, 10% ethyl acetate/n-hexane, Rf=0.6) to obtain (E)-10-heptyloxy-1-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidin-3-yl)-dec-3-en-1-one (No. 6804254; 336.2 mg, 3 steps, 75% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:15])[C:9]=2[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:7]=1)=[O:5])C.I[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]2=[O:37])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2.[NH4+].[OH-]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([N:8]2[C:9]3[C:10](=[O:15])[N:11]([C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]5=[O:37])=[CH:27][CH:26]=4)[CH2:12][CH2:13][C:14]=3[C:6]([C:4]([OH:3])=[O:5])=[N:7]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Reactant: O=C1CCCCN1c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(C(=O)O)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of 1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (50, 2.0 g, 6.4 mmol), 1-(4-iodo-phenyl)-piperidin-2-one (60, 2.5 g, 8.3 mmol, 1.3 equiv), and K2CO3 (325 mesh powder, 1.8 g, 12.8 mmol, 2.0 equiv) in DMSO (35 mL) was degassed three times under a steady nitrogen stream before being treated with CuI (244 mg, 1.3 mmol, 20% equiv) and 8-hydroxyquinoline (189 mg, 1.3 mmol, 20% equiv) under N2. The resulting reaction mixture was subsequently degassed three times again before being warmed up to 125° C. for 10 h. When HPLC showed the coupling reaction was complete, the reaction mixture was cooled down to 5–10° C. before being treated with 14% NH4OH aqueous solution (30 mL) and ethyl acetate (30 mL) at 5–10° C. with good stirring. The mixture was stirred for an additional 1 h at 5–10° C. The mixture was filtered through a Celite® bed and the Celite® bed was washed with water (2×10 mL). The two layers of the filtrates were separated, and the aqueous layer was acidified by 1 N aqueous HCl solution to pH=4. The mixture was subsequently stirred at 5–10° C. for an additional 1 h. The solids were collected by filtration, washed with water (2×5 mL), and dried in vacuo at 40–45° C. for 12 h to afford the crude desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (61, 2.0 g, 2.95 g theoretical, 68%), which was found to be pure enough to do the following reaction without further purification. For 61, CIMS m/z 461 (M++H, C25H24N4O5).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:40]=2)[CH:35]=[CH:34]1>COCCOC.O.[Pd].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>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:39]2[CH:40]=[C:41]3[C:36]([CH:35]=[CH:34][N:33]3[CH3:32])=[CH:37][CH:38]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: Cn1ccc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ccn(C)c2c1
Yield: 73.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.129 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.076 g (61%) of the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1>>[CH3:26][C:24]1[N:25]=[C:21]([NH:20][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:18]=[N:17][CH:16]=[N:15][CH:14]=3)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[S:22][CH:23]=1
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncnc1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cncnc2)n1

Procedure:
The title compound, was prepared in accordance with the general method of Example 78, step 2 from 6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-amino-4-methylthiazole to yield the final compound as an off-white solid, MS (ISP): m/e=327.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25].[OH-].[Na+]>N1C=CC=CC=1.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH:20][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:21][CH:22]=1)([OH:3])=[O:2]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Yield: 59.5 %

Procedure:
A solution of 1.5 g of 2-(4-carboxybenzamido)-4-aminobenzoic acid in 50 ml of pyridine was mixed with 3.2 g of isobutyroyl chloride and the mixture was heated at 50° to 60° C. for a period of 2 hours. The reaction mixture was further mixed with a solution of 4 g of sodium hydroxide in 20 ml of water and concentrated under vacuum. The residue was diluted with water and hydrochloric acid was used to adjust the pH of the dilution between 1 and 2. The precipitating crystal was filtered, washed with water and recrystallized from a solvent mixture of methanol and water to thereby produce 1.1 g of 2-(4-carboxybenzamido)-4-isobutyramidobenzoic acid having a melting point in the range of from 312° to 314° C. (decompose).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([NH2:12])[CH:6]=1.C([O:16][C:17](=O)[CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19](=O)[CH3:20])C.O1CCOCC1.C([O-])(=O)C.[Na+]>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:13])=[C:6]2[C:7]=1[NH:12][C:19]([CH3:20])=[C:18]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[C:17]2=[O:16]
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: COC(=O)Cc1ccc(Cl)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1[nH]c2c(Cl)ccc(CC(=O)O)c2c(=O)c1Cc1ccc(Cl)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenyl)acetic acid methyl ester (1.0 g), 2-(4-chlorobenzyl)-3-oxobutyric acid ethyl ester (1.3 g), polyphosphoric acid (5 mL) and dioxane (10 mL) was heated at 130° C. for 1.5 hours. The mixture was diluted with water and the pH of this solution adjusted to 3 by the addition of sodium acetate. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, ethyl acetate and methanol (1:0:0 to 10:1:0 to 1:1:0 to 20:0:1 and 0:0:1 by volume) to afford title compound, 0.60 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][S:10]([CH3:12])=[O:11].Cl.[N:15]([O-])=O.[Na+]>O>[CH3:12][S:10]([C:9]1[C:8](=[O:13])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][N:15]=1)=[O:11]
Reactant: CS(=O)CC(=O)c1ccccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)c1n[nH]c2ccccc2c1=O
Temperature: 20 °C

Procedure:
A solution of 5.0 g (0.025 mole) of 2'-amino-2-(methylsulfinyl)-acetophenone, 30 ml (0.03 mole) of cold (15°C) 1N hydrochloric acid and 100 ml of cold water cooled to 5°C. A solution of 2.07 g (0.03 mole) of sodium nitrite in 10 ml of water was added over a period of 3 minutes with stirring, keeping the temperature at 5°C. A deep red color developed as yellow solid separated. The mixture was allowed to warm up to 20°C. After 15 minutes at 20° the product was filtered, washed with water, 2-propanol and then ether. Wt 5.0 g (64%) mp. 266°-269°. Recrystallization from N,N-dimethylformamide gave pure, white crystals melting at 274°-276°C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:32]([OH:34])=[O:33])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:35][C:36]1C=NC2C(C=1)=CC=CC=2.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)(Cl)=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(Cl)Cl>[N:35]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[C:9]([C:17]([NH2:19])=[O:18])[CH:36]=1.[C:1]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:32]([OH:34])=[O:33])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: Nc1cnc2ccccc2c1
Agent: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cold solution (0° C.) of N-Boc-phenylalanyl-Nδ-Boc-ornithine (0.2 g, 0.4 mmol), 3-aminoquinoline (0.082 g, 0.57 mmol), diisopropylethylamine (0.103 mg, 0.8 mmol), 4-(dimethylamino)pyridine (5 mg, 0.04 mmol), and methylene chloride (3 mL) was treated dropwise with phosphorus oxychloride (0.5 mmol). The reaction was stirred at 0° C. for 1 hr and ethyl acetate (20 mL) was added. The organic layer was washed with water (2×20 mL), 1N hydrochloric acid (2×10 mL), saturated sodium bicarbonate (2×10 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate adsorbed onto 100 mg of silica gel and applied to a column prepacked with silica gel. The column was eluted with ethyl acetate/hexane (70:30, v:v) to afford titled compound (51 mg) as an oil: 1H NMR (400 MHz, CDCl3) δ1.42-1.55 (18H), 1.6-1.8 (1H), 2.0-2.1 (1H), 3.1-3.2 (4H), 3.3-3.4 (1H), 4.19-4.21 (1H), 4.70-4.80 (1H), 5.0-5.15 (1H), 7.21-7.29 (5H), 7.53-7.55 (1H), 7.63-7.65 (1H), 7.79-7.81 (1H), 8.05-8.07 (1H), 8.74 (1H), 8.94 (1H); mass spectrum (relative intensity) m/e 606 (100, M+1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH3:2].C([O-])(=O)C.[NH4+:35].[NH4+].[OH-]>O>[NH4+:6].[OH-:3].[NH2:35][C:9]1[C:8]2[N:22]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:25])[CH3:26])[C:7]=2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=1
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)(C)NC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CC(C)(C)NC(C)=O
Temperature: 160 °C
Reaction time: 24 h
Yield: 146.6 %

Procedure:
A pressure flask was charged with N-{2-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]-1,1-dimethylethyl}acetamide (980 mg, 2.39 mmol) and ammonium acetate (1.25 g). The flask was sealed and heated to 160° C. The solids soon melted to give a viscous oil and heating was continued for 24 h. The reaction mixture was cooled and treated with H2O and NH4OH solution until pH reached ˜12. The mixture was then extracted with CHCl3 (3×). The combined organic portions were washed with brine, dried with Na2SO4 and concentrated. Column chromatography (SiO2, 5% MeOH/CHCl3 saturated with NH4OH) gave N-{2-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]-1,1-dimethylethyl}acetamide (584 mg) as a tan foam. MS m/z 334 (M+H). 1H NMR (300 MHz, CDCl3) δ5.57 (s, 1H), 4.92 (s, 2H), 4.77 (s, 2H), 4.71 (br s, 2H), 3.62 (q, J=7.0 Hz, 2H), 2.44 (s, 6H), 1.96 (s, 3H), 1.30 (s, 6H), 1.24 (t, J=7.0 Hz, 3H).
Reaction SMILES: COC([CH:5]1[C:12](=[O:13])[CH2:11][C:8]2([CH2:10][CH2:9]2)[NH:7][C:6]1=[O:14])=O>C(#N)C.O>[CH2:9]1[C:8]2([CH2:11][C:12](=[O:13])[CH2:5][C:6](=[O:14])[NH:7]2)[CH2:10]1
Reactant: COC(=O)C1C(=O)CC2(CC2)NC1=O
Solvent: O
Solvent: CC#N
Product: O=C1CC(=O)NC2(CC2)C1
Yield: 86 %

Procedure:
5,7-Dioxo-4-aza-spiro[2.5]octane-6-carboxylic acid methyl ester (162 mg; 0.852 mmol) is refluxed in acetonitrile/water (3 ml; 9:1) for 1 hour. The reaction mixture is evaporated to dryness and taken up in EtOAc/MeOH, filtered from undissolved material and evaporated to yield the title compound as light-brown solid (102 mg; 85%). 1H-NMR (400 MHz; DMSO-d6): 8.28 (s, 1H); 3.59 (s, 2H); 2.48 (s, 2H); 0.83 (m. 2H); 0.70 (m, 2H). MS (m/z) ES+: 140 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:7][CH:8]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:10]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:9]2[CH:10]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of ethyl 3-[(2-aminoethyl)amino]-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (90 mg, 0.284 mmol) and triethylamine (59 μL, 0.426 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (26 μL, 0.341 mmol) in dichloromethane (1 mL) dropwise. The reaction mixture was warmed to room temperature and stirred one hour. The reaction mixture was quenched with ice and diluted with dichloromethane. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5%, methanol in dichloromethane) provided ethyl 5-[(4-fluorophenyl)methyl]-3-({2-[(methylsulfonyl)amino]ethyl}amino)-2-pyridinecarboxylate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1 H), 7.87 (t, J=5.6 Hz, 1 H), 7.13 (dd, J=8.3, 5.5 Hz, 2 H), 6.97 (t, J=8.7 Hz, 2 H), 6.89 (s, 1 H), 4.93 (m, 1 H), 4.39 (q, J=7.1 Hz, 2 H), 3.91 (s, 2 H), 3.38 (m, 2 H), 3.33 (m, 2 H), 2.94 (s, 3 H), 1.41 (t, J=7.1 Hz, 3 H); MS m/z 396 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:20][C@@H:19]2[C@@:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH2:14][C:15]3([CH2:18]2)[CH2:17][CH2:16]3)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:25]([O:24][C:22]([NH:21][C@@:13]12[CH2:14][C:15]3([CH2:16][CH2:17]3)[CH2:18][C@@H:19]1[CH2:20][NH:11][CH2:12]2)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@]12CN(C(=O)OCc3ccccc3)C[C@H]1CC1(CC1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@]12CNC[C@H]1CC1(CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
A 10% palladium-carbon catalyst (45.6 mg, 30 wt %) was added to a solution of (1S,5R)-3-benzyloxycarbonyl-1-tert-butoxycarbonylaminospiro(3-azabicyclo[3.3.0]octane-7,1′-cyclopropane) (152 mg, 0.393 mmol) in methanol (3.93 ml) in a nitrogen atmosphere. After the atmosphere was replaced with hydrogen, the mixture was stirred at room temperature for 30 minutes. After the atmosphere was replaced with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure to give 97.9 mg of the title compound as a transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]3)[CH:14]=2)[CH:10]=[N:9][CH:8]=1.C(O)(=O)C.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.CN1C(=O)CCC1>[CH2:34]([NH:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([NH:19][C:15]2[CH:14]=[C:13]([C:11]3[CH:10]=[N:9][CH:8]=[C:7]([NH:6][CH2:5][C:4]4[CH:27]=[CH:28][CH:29]=[C:2]([F:1])[CH:3]=4)[N:12]=3)[CH:18]=[CH:17][N:16]=2)[CH2:25][CH2:24]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cncc(NCc4cccc(F)c4)n3)ccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Fc1cccc(CNc2cncc(-c3ccnc(N[C@H]4CC[C@H](NCc5ccccc5)CC4)c3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To trans-N1-(4-(6-(3-fluorobenzyl amino)pyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine (19 mg, 0.048 mmol) was added NMP (0.6 ml), acetic acid (0.042 ml, 0.726 mmol) and benzaldehyde (10.27 mg, 0.097 mmol). The resulting reaction mixture was stirred overnight at ambient temperature. To the srirred reaction mixture was added sodium triacetoxyborohydride (41.0 mg, 0.194 mmol) and the resulting mixture was stirred overnight (24 hours) at ambient temperature. To the reaction mixture mixture then was added additional sodium triacetoxyborohydride (21.0 mg, 0.099 mmol) and the resulting mixture was stirred for an additional 2 more hours. To the crude mixture then was added 0.8 ml of DMSO, filtered and purified by prep LC. After lyophilization, 7.0 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 483.2 (MH+), retention time=0.65 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.35-1.51 (m, 2 H) 1.51-1.69 (m, 2 H) 2.04-2.36 (m, 4 H) 3.08-3.18 (m, 1 H) 3.56-3.70 (m, 1 H) 4.16 (s, 2 H) 4.60 (s, 2 H) 6.82-6.93 (m, 1 H) 7.03 (d, J=9.67 Hz, 1 H) 7.11 (d, J=7.62 Hz, 1 H) 7.19-7.29 (m, 1 H) 7.32 (d, J=6.74 Hz, 1 H) 7.35-7.46 (m, 5 H) 7.54 (s, 1 H) 7.80 (d, J=6.74 Hz, 1 H) 7.97 (s, 1 H) 8.25 (s, 1 H)
Reaction SMILES: C(N1C2C(=CC(C)=CC=2)C(O)([CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17](OC)=[C:16]([O:24][CH3:25])[CH:15]=2)C1=O)C.C([O:36][CH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([Cl:46])[CH:44]=2)[N:39]([CH2:47][CH2:48][CH2:49][CH3:50])[C:38]1=[O:51])(=O)C1C=CC=CC=1.COC1C=C(C=C(OC)C=1)CBr>>[CH2:47]([N:39]1[C:40]2[C:45](=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[C:37]([CH2:13][C:14]2[CH:15]=[C:16]([O:24][CH3:25])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=2)([OH:36])[C:38]1=[O:51])[CH2:48][CH2:49][CH3:50]
Reactant: CCN1C(=O)C(O)(Cc2cc(OC)c(OC)c(OC)c2)c2cc(C)ccc21
Reactant: CCCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Agent: COc1cc(CBr)cc(OC)c1
Product: CCCCN1C(=O)C(O)(Cc2cc(OC)cc(OC)c2)c2cc(Cl)ccc21

Procedure:
This compound was made in an analogous fashion to 1-ethyl-3-hydroxy-5-methyl-3-(3,4,5-trimethoxybenzyl)indolin-2-one using 1-butyl-5-chloro-2-oxoindolin-3-yl benzoate and 3,5-dimethoxy benzyl bromide (purchased from Fisher Scientific). 1H NMR δ 7.25 (m, 2H) 6.61 (d, 1H), 6.24 (s, 1H), 6.06 (s, 2H), 3.66 (m, 7H), 3.23 (m, 2H), 3.16 (d, 1H), 1.63 (bs, OH), 1.35 (m, 2H), 1.17 (m, 2H), 0.96 (t, 3H). Calculated mass for C21H24ClNO4, 389.14. Observed 412.2 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]([C:19]#[N:20])=[C:17]([N:21]=[CH:22][N:23](C)C)[NH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)N>CO>[Cl:27][C:28]1[CH:34]=[C:33]([NH:20][C:19]2[N:23]=[CH:22][N:21]=[C:17]3[NH:16][N:15]=[C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]4)[C:18]=23)[CH:32]=[CH:30][CH:29]=1
Reactant: CN(C)C=Nc1[nH]nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)CC1

Procedure:
With the exclusion of air, 16.2 9 (46.6 mmol) of N′-[3-(4-tert-butoxycarbonyl-piperazin-1 -yl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethyl-formamidine in 130 ml methanol are heated to boiling with 11.47 g (70 mmol) of 3-chloro-aniline hydrochloride. After 9 hours the reaction mixture is cooled, filtered and washed with methanol and DIPE. Stirring the crude product in boiling ethanol, cooling and filtration yield 4-(3-chloro-phenylamino)-3-(4-tert-butyloxycarbonyl-piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=15.7; IR (KBr) interalia 1706 s, 1631 s, 1610 s, 1589 s, 1508 m, 1482 s, 1425 m, 1364 m, 1304 m, 1283 m, 1245 m, 1170 m, 1122 m.