Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:5][C:6](=[O:21])[C@@H:7]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O.[OH-].[Li+]>O1CCCC1.O>[C:12]([O:11][C:9]([NH:8][C@@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:27])=[O:2])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H](CC(C)(C)C)NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@H](NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
N-(tert-Butoxycarbonyl)-3-tert-butyl-D-alanyl-3-tert-butyl-L-alanine methyl ester (Example 8A, 36 g, 93.1 mmol) is dissolved in tetrahydrofuran p.a. (279 ml). At about 10° C., a solution of lithium hydroxide monohydrate (7.82 g, 186.3 mmol, 2 equivalents) in water (187 ml) is slowly added dropwise. When the HPLC chromatogram (Method 2) shows complete conversion (about 20 h), the reaction mixture is freed of the THF at 200 mbar and then extracted with methyl tert-butyl ether (200 ml). The organic phase is diluted with ethyl acetate (500 ml) and then water is added and the mixture is subsequently adjusted cautiously to pH 3-4 with 1 N aqueous hydrochloric acid. The combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, evaporated in vacuo and dried under high vacuum. 97.4 g (97% of theory) of the title compound are added.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([N:14]=[N+:15]=[N-:16])=[O:13])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:17][N:8]1[C:7]2[C:2]([CH3:1])=[CH:3][C:4]([C:12]([N:14]=[N+:15]=[N-:16])=[O:13])=[CH:5][C:6]=2[O:10][C:9]1=[O:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)N=[N+]=[N-])cc2oc(=O)[nH]c12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)N=[N+]=[N-])cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
550 mg (2.50 mmol) 4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carboxylic acid azide and 400 mg (2.90 mmol) potassium carbonate were stirred in DMF for 20 min at RT. Then 0.200 mL (3.21 mmol) of methyl iodide were added and the mixture was stirred for 1.5 h at RT. Water was added to the reaction mixture, the precipitate formed was suction filtered and dried.
Reaction SMILES: CN(OC)[C:3](=[O:17])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].CC(C[AlH]CC(C)C)C.S(=O)(=O)(O)O.C(OCC)(=O)C>C1COCC1>[O:15]1[C:16]2[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][CH:3]=[O:17])=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14]1
Reactant: CON(C)C(=O)CC(C)(C)c1cccc2c1OCC2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CC=O)c1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97.7 %

Procedure:
3-(2,3-Dihydrobenzofur-7-yl)-3-methylbutanoic acid N,O-dimethylhydroxylamide (950 mg) in THF (10 mL) was treated with DIBAL (1 M in toluene, 4.32 mL) at −78° C. After 45 minutes, the mixture was warmed to 0° C. for 5 minutes. 7 mL of aqueous sulfuric acid (1 M) and 20 mL of ethyl acetate were added. The organic phase was separated and the aqueous layer was extracted with 20 mL of ethyl acetate. The combined organic phases were dried over magnesium sulfate. The solvent was removed to give 720 mg (98%) of 3-(2,3-dihydrobenzofur-7-yl)-3-methylbutanal as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH3:25])[CH2:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:26]1([C:2]2[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH3:25])[CH2:19]4)=[CH:14][CH:13]=3)(=[O:9])=[O:10])=[CH:6][CH:7]=2)[CH2:28][CH2:27]1
Reactant: OB(O)C1CC1
Reactant: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(Br)cc3)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(C4CC4)cc3)cc2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
0.3 g of 4-bromo-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide (0.71 mmol), 0.079 g of cyclopropylboronic acid (0.92 mmol), 0.526 g of potassium phosphate (2.48 mmol) and 0.02 g of ricyclohexylphosphin were dissolved in a mixture of 4 ml of toluene and 2 ml of water. After addition of 0.008 g of palladium(II)-acetate (0.04 mmol), the reaction mixture was stirred for 1 h at 100° C. in the microwave (CEM). The solution was decanted, the remaining suspension containing the catalyst washed again with ethyl acetate, the combined solvent extracts evaporated to dryness, redissolved in ethyl acetate and washed with water. The aqueous phase was reextracted once with ethyl acetate, the organic layers combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified via silica gel chromatogrphay with dichloromethane, dichloromethane-methanol (5.5%). Fractions containing the product were combined, the solvent removed, to yield 0.066 g of the title product.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH2:30]([OH:33])[CH2:31][CH3:32]>O1CCOCC1.CN(C=O)C>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][C:2]([O:33][CH2:30][CH2:31][CH3:32])=[N:3][CH:4]=3)[S:10][C:11]=2[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:16][CH:15]=1
Reactant: CCCO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCCOc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and propanol in dioxane and DMF. ES-MS m/e (%): 429 (M+H+, 100).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[OH:13][C:14]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[CH2:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C1C=CN=CC=1.C(#N)C>[CH2:27]([O:17][C:16](=[O:18])[C:15]1[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]=1[OH:13])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(O)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 mmol of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride was slowly added to a stirred suspension of 5 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid, 5 mmol of benzyl alcohol and 0.5 mmol of 4-dimethylaminopyridine in 10 ml acetonitrile. The mixture was stirred overnight at room temperature, concentrated and treated with 10 ml of water. A few drops of diluted hydrochloric acid were added to acidify the solution. The resulting solid was filtered and then purified by chromatography (SiO2; ethyl acetate/cyclohexane 3:7) to yield the title compound as a colorless solid. MS (m/e): 305.0 (M−H, 100%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([CH2:35][C:36]#[N:37])[CH:32]=[CH:33][CH:34]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([C:29]4[CH:30]=[C:31]([CH2:35][C:36]#[N:37])[CH:32]=[CH:33][CH:34]=4)[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cccc(CC#N)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: [Cs+]
Solvent: COCCOC
Product: COc1ccc(Cn2nc(C)c3cc(-c4cccc(CC#N)c4)cnc32)cc1
Temperature: 80 °C

Procedure:
The starting material 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (136 mg, 0.41 mmol, 1 eq) and 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (156) (100 mg, 0.41 mmol, 1 eq) in DME (10 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (260 mg, 0.82 mmol, 2 eq) followed by addition of Pd(PPh3)4 (15 mg, 0.03 mmol), degassing and purging under argon for additional 10 min. The reaction mixture was heated at 80° C. for 12 h in a sealed tube. After completion of the reaction, the solvents were removed and reaction mixtures were extracted into EtOAc, dried over Na2SO4 and the solvents distilled off. The crude material was submitted for flash column purification using 20% EtOAc in hexane to obtain off-white solid compound 2-(3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acetonitrile 157.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[H][H].[N+:14]([C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=O)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[CH2:20][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)([O-:16])=[O:15]
Reactant: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Reactant: [H][H]
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
Sodium borohydride (3.36 g, 89 mmol, 2.1 eq.) was ground, placed in a nitrogen-flushed flask and suspended in THF (120 mL). After cooling to ˜0° C., boron trifluoride etherate (11.3 mL, 89 mmol, 2.1 eq.) was added via syringe. This reaction is mildly exothermic and some hydrogen evolution was noted. 4-(3,4-Dinitrobenzoyl)morpholine (11.91 g, 42 mmol, 1.0 eq.) was added as a solid in one portion, the vessel being rinsed with an additional portion of THF (20 mL). The ice-bath was removed and the suspension stirred at r.t. for 3 h before cooling again in ice. Methanol (100 mL) was added cautiously (hydrogen evolution) then the mixture was brought to reflux for 1 h. The mixture was concentrated in vacuo then the residue was partitioned between ethyl acetate (100 mL) and 1:1 saturated sodium bicarbonate solution/water (100 mL). The organic phase was separated, washed with water (50 mL) then brine (100 mL) and dried (MgSO4). The initial bicarbonate wash was extracted a second time with ethyl acetate (50 mL), this extract then being washed with the same aqueous washes used for the first extract before drying (MgSO4), combination and concentration to afford 10.97 g of crude material. Recrystallisation from methanol (45 mL, 10 mL wash) gave the title compound (9.34 g, 83%).
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:51]([O:58][C:59](=[O:62])[CH2:60][NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][C:59](=[O:62])[CH2:60][NH:61][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole), HOBt (338 mg, 2.5 m mole) and glycine benzylester p-toluene sulfonic acid salt (1.0 g, 3 m mole) were suspended in DMF (10 ml), and WSC (0.5 ml) was dropwise added thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling, and next, overnight at room temperature. To the reaction solution ethyl acetate (100 ml) was added and the mixture was washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The thus dried solution was distilled under reduced pressure to give an oily dibenzylphosphoryl-L-alanyl-L-prolyl-glycine benzylester material (1.5 g). The oily material gave a single spot with Rf 0.7 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine and heating).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:12](Cl)([CH3:15])(=[O:14])=[O:13].O>C(Cl)Cl>[C:1]([NH:5][S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of tert-butylamine (6.8 ml) and pyridine (7.8 ml) in methylene chloride (50 ml) was added dropwise mesyl chloride (5.0 ml) at 0° C. The mixture was stirred for 30 minutes. The reaction mixture was poured into water and then extracted with methylene chloride. The organic layer was concentrated. The residue was purified by column chromatography to give the title compound (5.2 g) having the following physical data.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:16][CH2:17][CH3:18])[CH2:9][C:10]([NH:12][CH:13]1[CH2:15][CH2:14]1)=[O:11])(C)(C)C.[ClH:20].[O:21]1CCOCC1>>[ClH:20].[NH2:7][C@@H:8]([CH2:16][CH2:17][CH3:18])[CH:9]([OH:21])[C:10]([NH:12][CH:13]1[CH2:15][CH2:14]1)=[O:11]
Reactant: CCC[C@@H](CC(=O)NC1CC1)NC(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: Cl
Product: CCC[C@H](N)C(O)C(=O)NC1CC1
Reaction time: 1 h

Procedure:
To tert-butyl-(3S)-1-(cyclopropylamino)-1-oxohexan-3-ylcarbamate (75 mg, 0.26 mmol) was added 4.0 M HCl in dioxane (6.0 mL). After 1 hour, the reaction mixture was concentrated and dried to give the (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide HCl salt as a white solid. To this salt in dichloromethane/N,N-dimethylformamide (10:3, 13 mL) was added (2S,4R)-1-(tert-butoxycarbonyl)-4-(6-ethoxyisoquinolin-1-yloxy)-pyrrolidine-2-carboxylic acid (106 mgs, 0.26 mmol), O (7 azabenzotriazol 1 yl) 1,1,3,3 tetramethyl-uronium hexafluorophosphate (HATU) (119 mg, 0.31 mmol) and diisopropylethylamine (0.15 mL, 0.78 mmol). After 1 hour at room temperature reaction mixture was diluted with ethyl acetate and washed with 1N HCl (2×), sodium bicarbonate (1×), and brine (1×). The ethyl acetate layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to give (2S,4R)-1-(tert-butyl-2-((3S)-1-cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(6-ethoxyisoquinolin-1-yloxy)pyrrolidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:26]=[C:12]2[C:13]([NH:17][C:18]3[CH:23]=[C:22]([NH:24][CH3:25])[N:21]=[CH:20][N:19]=3)=[N:14][CH:15]=[CH:16][C:11]2=[N:10]1.ClC1N=CN=C(NC2C3=CN(C4C(Cl)=CC=CC=4Cl)N=C3C=CN=2)C=1.[F:52][CH:53]1CN[CH2:54]1.CCN(C(C)C)C(C)C>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[CH:26]=[C:12]2[C:13]([NH:17][C:18]3[CH:23]=[C:22]([N:24]4[CH2:54][CH:53]([F:52])[CH2:25]4)[N:21]=[CH:20][N:19]=3)=[N:14][CH:15]=[CH:16][C:11]2=[N:10]1
Reactant: CNc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Reactant: FC1CNC1
Agent: Clc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Solvent: CCN(C(C)C)C(C)C
Product: FC1CN(c2cc(Nc3nccc4nn(-c5c(Cl)cccc5Cl)cc34)ncn2)C1
Yield: 93 %

Procedure:
Following the procedure described for N-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]-N′-methylpyrimidine-4,6-diamine, (6-chloropyrimidin-4-yl)-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]amine and 3-fluoroazetidine with added DIPEA (103 μL, 0.6 mmol) were reacted to afford the title compound as a yellow solid (81 mg, 93% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.28 (br s, 1H), 9.14 (s, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.70 (dd, J=9.1, 7.3 Hz, 2H), 7.16 (br s, 1H), 5.62-5.46 (m, 1H), 4.38 (ddd, J=21.3, 10.5, 5.9 Hz, 2H), 4.14 (d, J=10.5 Hz, 1H), 4.08 (d, J=10.5 Hz, 1H). LCMS (Method B): RT=3.16 min, m/z: 430 [M+H+].
Reaction SMILES: C(NC1C=CN=C(C(=O)C(SC)=O)C=1)=O.[OH-].[Na+].[CH:18]([NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27](=O)[C:28]([OH:30])=[O:29])[CH:22]=1)=[O:19].Cl.[CH3:33][O:34][NH2:35]>CO>[CH:18]([NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27](=[N:35][O:34][CH3:33])[C:28]([OH:30])=[O:29])[CH:22]=1)=[O:19]
Reactant: O=CNc1ccnc(C(=O)C(=O)O)c1
Reactant: CON
Agent: CSC(=O)C(=O)c1cc(NC=O)ccn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C(C(=O)O)c1cc(NC=O)ccn1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A mixture of S-methyl 2-(4-formamidopyridin-2-yl)thioglyoxylate (1.07 g.), methanol (20 ml.) and 1 N aqueous solution of sodium hydroxide (5.7 ml.) was stirred for 50 minutes at ambient temperature to give a solutions containing 2-(4-formamidopyridin-2-yl)glyoxylic acid. To the solution was added O-methylhydroxylamine hydrochloride (438 mg.), and the mixture was stirred for an hour at ambient temperature. After the removal of the solvent from the reaction mixture, to the residue was added water (5 ml.), and the mixture was washed with ethyl acetate and then water was distilled off. The remaining water in the residue was azeotropically removed with ethanol and benzene in turn to give a pale brown powder of 2-(4-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (960 mg.).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([CH3:14])(O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([F:28])([CH3:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCN(Cc1ccccc1)Cc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
Treat a −78° C. solution of 4-(dibenzylamino)-2-methylbutan-2-ol (110.0 g, 0.39 mol) in DCM (1 L) drop-wise with diethylaminosulfur trifluoride (75 g, 0.47 mol) under N2, allow it to warm to RT and stir overnight. Re-cool the mixture to −78° C., treat drop-wise with saturated NaHCO3 (300 mL), warm to RT, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (0.1-0.2% EtOAc/pet ether) to afford the title compound (44.0 g, 40% yield). MS (m/z): 286.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[O:24])=[CH:12][CH:13]=1)=[O:6].C([O-])([O-])O[CH2:31][CH3:32].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH:18]=[C:19]3[O:24][CH2:31][CH3:32])=[CH:12][CH:13]=1)=[O:6]
Reactant: CCOC([O-])[O-]
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=O)nc1)c1ccc(Cl)c(Cl)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CCOC1=CCc2c(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cccc21

Procedure:
3.5 g of 3,4-dichloro-N1-{6-(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl}benzamide obtained in Example 1 was suspended in 140 ml of ethanol. To the suspension, 14 ml of ethyl orthoformate, 820 mg of (±)-10-camphorsulfonic acid and 3.5 g of 4A molecular sieves were added and the mixture was heated at reflux for 30 minutes. After air cooling, the reaction mixture was filtered. To the filtrate, 8.5 ml of an aqueous 1N sodium hydroxide solution was added and the solvent was distilled off under reduced pressure. To the resulting residue, 100 ml of ethyl acetate was added and the solution was washed in turn with water and a saturated sodium hydrogencarbonate solution and then dried over magnesium sulfate. After drying, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (4:1)) to obtain the titled compound (white powder, 530 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[O:4].[CH2:19]([N:23]=[C:24]=[O:25])[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:19]([NH:23][C:24]([NH:18][S:15]([CH2:14][C:6]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:16])=[O:25])[CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CS(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)Cc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 7.7 g of the product from Example 4, 3.5 g of n-butyl isocyanate, and 4.8 g anhydrous potassium carbonate in 100 ml of methyl ethyl ketone was stirred at reflux temperature for 4 hours. After cooling to room temperature, the reaction mixture was concentrated to approximately one-third volume and diluted with 150 ml of water. The resulting solid was collected by filtration and washed with one portion of water and one portion of n-butyl chloride. The yield of N-[(n-butyl)aminocarbonyl]-2-(methoxycarbonyl)-6-nitrophenylmethanesulfonamide, m.p. 144°-150°, was 9.1 g as a tan solid; IR(nujol): 1725, 1665 cm-1, NMR (CDCL3 /DMSO-d6): δ 0.6-1.7 (7H, m), 2.9-3.4 (2H, m), 4.0 (3H, s, CO2CH3), 5.7 (2H, s, --CH2 --), 7.4-8.3 (3H, m), 10.5 (1H, br s, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18]C)[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=2)=[N:10]1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2-c1c(F)cccc1F
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of (4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (140 mg) in acetonitrile (6 mL) were added sodium iodide (139 mg) and chloro(trimethyl)silane (0.475 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate to ethyl acetate) to give the title compound (80.2 mg).