Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.O1CCCC1.Br[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=1>C(OCC)(=O)C.Cl.[Cl-].[Zn+2].[Cl-]>[F:25][C:20]1[CH:19]=[C:18]([C:3]2[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=2)[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: Cc1ccc(Br)cc1F
Reactant: CCCCCC
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1.6M-n-Butyllithiumhexane solution (30 ml) is added to tetrahydrofuran (30 ml) the tetrahydrofuran is chilled to −78° C. under a nitrogen environment beforehand. Subsequent to this addition, a tetrahydrofuran (30 ml) solution of 4-bromo-2-fluorotoluene (9.21 g) is added. Then, the solution is stirred for one hour at −78° C. A tetrahydrofuran (30 ml) solution of zinc chloride (6.64 g), which had been heat-dissolved and dehydrated under reduced pressure, is added to the solution at −78° C. and the solution is stirred for one hour at room temperature. This solution is added to a tetrahydrofuran (30 ml) solution of iodobenezen (6.63 g) and tetrakis(triphenylphosphyne)palladium (0.52 g) at room temperature, and the solution is stirred for a day and a night. The reaction solution is diluted with ethyl acetate (300 ml), 10% hydrochloric acid is added, and extraction is performed. After the organic layer is washed with a saturated saline solution and dried, it is concentrated. The residue is purified using silica gel column chromatography (eluate: hexane) and thus, oily 3-fluoro-4-methylbiphenyl (6.00 g) is obtained. 1H-NMR (CDCl3, δ): 2.31 (3H, d, J=1.8 Hz), 7.20-7.28 (3H, m), 7.34 (1H, m), 7.43 (2H, t), 7.55 (2H, d).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>[OH-].[Na+]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH2:15][CH:17]1[O:19][CH2:18]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCC1CO1
Reaction time: 96 h

Procedure:
0.376 mol (73.7 g) of 2-acetylamino-5-nitrophenol is dissolved in 375 ml of 1.1 N sodium hydroxide solution, and 300 ml of epichlorohydrin are then added. The reaction medium is left to stand for 96 hours at 20° C., with thorough stirring, and the expected product which has precipitated is then filtered off and washed with water. After recrystallisation from ethanol and drying in vacuo, it melts at 164° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([CH:46]2[CH2:48][CH2:47]2)[N:18](COCC[Si](C)(C)C)[C:19]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[CH3:29])[N:21]=1.Cl>CCO>[NH2:30][C@@H:28]([CH3:29])[CH2:27][NH:26][C:22]1[N:21]=[C:20]([C:19]2[NH:18][C:17]([CH:46]3[CH2:48][CH2:47]3)=[N:16][C:15]=2[C:3]2[C:2]([Cl:1])=[C:7]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)n(COCC[Si](C)(C)C)c2-c2ccnc(NC[C@H](C)NC(=O)OC(C)(C)C)n2)c1Cl
Agent: Cl
Solvent: CCO
Product: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)[nH]c2-c2ccnc(NC[C@H](C)N)n2)c1Cl
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 107.1 %

Procedure:
A solution of (S)-tert-butyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (116 mg, 0.14 mmol) in EtOH (2 mL) was treated with aqueous 6.0 N HCl solution (0.8 mL, 4.8 mmol) and the resulting reaction was heated to 60° C. for 30 minutes, then at room temperature for 40 minutes. The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. Further drying under high vacuum afforded (S)—N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide (80 mg, 0.15 mmol) as the HCl salt (4A-2) which was used without further purification: LCMS (m/z) 490.2 (MH+), tR=0.48 minute.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH3:13])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC(C)=O.O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[C:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])=[N:5][N:4]=[N:3]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCNCCCSc1nnnn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(CCCSc1nnnn1C)C(=O)C1CCCCC1
Reaction time: 2 h
Yield: 58.2 %

Procedure:
1-Methyl-5-[3-(N-ethylamino)propylthio]-1,2,3,4-tetrazole (1 g) is dissolved in a mixture of acetone (50 ml) and water (10 ml). To the mixture is added potassium carbonate (0.7 g) and thereto is added dropwise with stirring cyclohexanecarboxylic acid chloride (0.9 g) under ice-cooling. Stirring is continued for 2 hours under ice-cooling. After acetone is distilled off, water is added to the resulting residue and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. Chloroform is distilled off and then the residue is purified by column chromatography (Wakogel C-200), followed by eluting with chloroform to give 1-methyl-5-[3-(N-ethyl-N-cyclohexylcarbonylamino)propylthio]-1,2,3,4-tetrazole (0.9 g), colorless liquid, nD23.5 =1.5267.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-])=O.C(OCC)(=O)C>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Reaction time: 3 h
Yield: 104.3 %

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1-pyridin-3-yl-1H-indazole (0.79 mmol) in 10 mL of methanol was added 10 mL of ethyl acetate and 30 mg of platinum (IV) oxide. After shaking under 50 psi of H2 for 3 h, the mixture was filtered through a pad of Celite and concentrated in vacuo, affording 0.25 g of 5-(5-Amino-pyridin-2-yloxy)-1-pyridin-3-yl-1H-indazole
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].CC1(C)C(O)C(=O)OC1.C=O.C(=O)C(C)C.[C-]#N>>[C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7]
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O
Agent: C=O
Agent: CC(C)C=O
Agent: CC1(C)COC(=O)C1O
Product: CC(C)(CO)[C@H](O)C(=O)NCCC(=O)O

Procedure:
Pantothenic acid can be prepared by chemical synthesis, or biotechnologically by the fermentation of suitable microorganisms in suitable nutrient solutions. In the chemical synthesis, DL-pantolactone is an important compound. It is prepared in a multi-stage process from formaldehyde, isobutyraldehyde and cyanide. In further process steps, the racemic mixture is separated, D-pantolactone is subjected to a condensation reaction with β-alanine, and D-pantothenic acid is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[O:6])[CH:2]=[CH2:3].[OH-].[Li+]>C(O)(C)C>[CH2:1]([O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(CCCC(=O)OC)ccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Product: C=CCOC(=O)c1c(CCCC(=O)O)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
A solution of Example 11D (400 mg, 1.28 mmol) in isopropyl alcohol (5 mL) was treated with lithium hydroxide (1.0M, 1.28 mL, 1.28 mmol), stirred at room temperature for 1.5 hours, and partitioned between ethyl acetate and water. The aqueous layer was then acidified with 1N HCl, extracted with dichloromethane, dried (Na2SO4), filtered, and concentrated to provide 282.8 mg (74%) of the desired compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=4)[CH:20]=3)[CH2:14][CH2:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:49]2[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=2)[CH2:52][Cl:53])[CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:69].Cl>>[ClH:53].[ClH:69].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=4)[CH:20]=3)[CH2:16][CH2:17]2)[CH2:52][C:51]2[CH:54]=[CH:55][CH:56]=[C:49]([C:41]3[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:39]([O:38][CH3:37])[CH:40]=3)[CH:50]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(OC)cc(N(Cc2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)c1

Procedure:
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][N:13]1[C:17]([NH2:18])=[N:16][N:15]=[N:14]1.N1C=CC=CC=1.O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][C:17]1[N:13]([CH3:12])[N:14]=[N:15][N:16]=1)=[O:5]
Reactant: Cn1nnnc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: Cn1nnnc1NC(=O)c1ccc(Cl)cc1Cl

Procedure:
In a microwave oven, 209 mg (1.0 mmol) of 2,4-dichlorobenzoyl chloride, 198 mg (2.0 mmol) of 1-methyl-5-aminotetrazole and 237 mg (3 mmol) of pyridine in 3 ml of acetonitrile are stirred at 130° C. for 45 min. Water is then added, and the product is filtered off with suction and washed with ether. Yield 80 mg (30%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:15][CH3:16])[CH2:4][S:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C)[C@@H:24]([CH2:30][O:31]C(=O)C)[O:23][C@H:22]1[N:35]1[CH:43]=[N:42][C:41]2[C:36]1=[N:37][C:38]([Cl:45])=[N:39][C:40]=2Cl)(=O)C.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C2N=C(Cl)N=C(N[C@H](C)CSC3SC4C=CC=CC=4N=3)C=2N=C1)(=O)C.C[O-].[Na+]>CO>[S:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[S:5][CH2:4][C@H:3]([NH:2][C:40]1[C:41]2[N:42]=[CH:43][N:35]([C:36]=2[N:37]=[C:38]([Cl:45])[N:39]=1)[C@@H:22]1[O:23][C@H:24]([CH2:30][OH:31])[C@@H:25]([OH:26])[C@H:21]1[OH:20])[CH2:15][CH3:16]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC[C@@H](N)CSc1nc2ccccc2s1
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4nc5ccccc5s4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: CC[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 50.8 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-butylthio]benzothiazole hydrochloride (1.16 g, 4.2 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.57 g, 3.5 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosine using sodium methoxide in methanol. This provided the title N-[(R)-1-(2-benzothiazolyl)thio-2-butyl]-2-chloroadenosine (0.93 g, 51%) (following column chromatography), 1H NMR (DMSO-d6) δ 1.38 (3H, d, --CH2CH3), 1.65-1.86 (2H, m, --CH2CH3), 3.95 (1H, q, H-4'), 4.14 (1H, d, H-3'), 4.48-4.62 (2H, m, H-2' and --CHCH2H3), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.34, 7.45 (2H, 2t, Ar-H), 7.84, 8.0 (2H, 2d, Ar-H). HPLC retention time 21.8 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]#[N:9].[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C(OCC)(=O)C>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]#[N:9]
Reactant: N#CC1=C(N)CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC1CCCCC1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
To a cold solution of 2-aminocyclohex-1-enecarbonitrile (I-7a: 50 mg, 0.41 mmol) in methanol (3 mL) was added NaCNBH3 (103 mg, 1.64 mmol) and acetic acid (5 drops) at 0° C. The resulting mixture was stirred at room temperature for 16h. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated NaHCO3, brine, dried over anhydrous Na2SO4 and concentrated to afford 40 mg (78%) of diastereomeric mixture of 2-aminocyclohexanecarbonitrile (I-7b) as a gum.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]2[N:13]([N:15]=[CH:16][CH:17]=2)[CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:12]2[N:13]([N:15]=[CH:16][CH:17]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)cn2nccc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(O)cn2nccc12
Reaction time: 1 h

Procedure:
tert-butyl [6-(benzyloxy)pyrazolo[1,5-a]pyridin-4-yl]carbamate from Step 3 (140 mg, 0.363 mmol) was dissolved in absolute ethanol (5 ml). Palladium on carbon (77 mg, 0.073 mmol) was added and the mixture was placed under an atmosphere of hydrogen (balloon). After 1 h, the mixture was filtered through a 45 μm syringe filter and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford tert-butyl (6-hydroxypyrazolo[1,5-a]pyridin-4-yl)carbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(CCl)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: COc1cccc(Cn2ccc3ccc(CC(=O)O)cc32)c1

Procedure:
The titled compound (55 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 3-methoxybenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH2:21])[CH2:3]1.CCN(C(C)C)C(C)C.[N:32]1[N:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]2=[C:34]([C:41](Cl)=[O:42])[CH:33]=1>C1COCC1>[F:22][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[N:11]=[CH:10][C:9]=2[NH:21][C:41]([C:34]2[CH:33]=[N:32][N:36]3[CH:37]=[CH:38][CH:39]=[N:40][C:35]=23)=[O:42])[CH2:3]1
Reactant: C[Si](C)(C)COCCn1ncc(N)c1N1CCCC(F)(F)C1
Reactant: O=C(Cl)c1cnn2cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)COCCn1ncc(NC(=O)c2cnn3cccnc23)c1N1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine (1.2 g, 3.61 mmol) in 30 mL THF was added DIPEA (1.3 mL, 7.22 mmol) and pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (720 mg, 3.97 mmol) in THF (50 mL) at 0° C. After addition was complete, the mixture was warmed to room temperature, then stirred overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatogaphy (hexanes:EtOAc=3:1 to 1:1) to afford 1.0 g (60%) of N-(5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=478.2; 1H NMR (400 MHz, CDCl3) δ: 9.49 (s, 1H), 8.87 (dd, 1H), 8.75 (s, 1H), 8.71 (dd, 1H), 7.94 (s, 1H), 7.10 (dd, 1H), 5.40 (s, 2H), 3.67 (m, 6H), 2.06 (s, 2H), 1.93 (m, 2H), 0.95 (m, 2H), 0 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]=[CH:19][N:20]([S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[CH:6]2.CN(C)C(=O)C>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:16][NH:15][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:17]3[N:18]=[CH:19][N:20]([S:22]([C:25]4[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=4)(=[O:23])=[O:24])[CH:21]=3)=[O:1])[CH:4]=2)[CH:9]=1)=[O:14]
Reactant: CNC(=O)c1ccc2cc(C(O)c3cn(S(=O)(=O)c4ccc(C)cc4)cn3)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc(C(=O)c3cn(S(=O)(=O)c4ccc(C)cc4)cn3)ccc2c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 79.8 %

Procedure:
6-(Hydroxy(1-tosyl-1H-imidazol-4-yl)methyl)-N-methyl-2-naphthamide (8.2 g, 18.8 mmol) and manganese dioxide (14.7 g, 169.1 mmol) were added to N,N-dimethylacetamide (70 mL), and the mixture was stirred at 60° C. for 7 hr. The insoluble material was filtered off from the obtained reaction mixture at 60° C., and washed with N,N-dimethylacetamide (33 mL). The filtrate and washing were combined, and cooled to 40° C., water (49 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 0.5 hr or more, and then at room temperature for 1 hr or more to give crystals. The obtained crystals were collected by filtration, and washed with water (51 mL) to give wet crystals. The obtained wet crystals were dried under reduced pressure at an outside temperature of 50° C. to give crude crystals (6.6 g). Ethyl acetate (66 mL) were warmed to 40° C., and the crude crystals (6.6 g) were added thereto. The obtained mixture was warmed to 50° C., and stirred for 0.5 hr or more, and 13 mL of the solvent was evaporated under reduced pressure. The obtained residue was allowed to cool to room temperature, diisopropyl ether (53 mL) was added dropwise thereto at the same temperature, and the mixture was stirred to give crystals. The obtained crystals were collected by filtration, and washed with a mixed solvent (20 mL) of diisopropyl ether/ethyl acetate (1:1, volume ratio) to give wet crystals. The obtained wet crystals were dried under reduced pressure at an outside temperature of 50° C. to give N-methyl-6-[(1-tosyl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (6.5 g, 15.0 mmol). yield 79%.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH2:4][CH3:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:39]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[NH2:46])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C.C(Cl)CCl>[C:39]([O:43][C:44](=[O:51])[C@@H:45]([NH:46][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([NH:6][CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)[CH2:47][CH:48]([CH3:49])[CH3:50])([CH3:41])([CH3:40])[CH3:42]
Reactant: CCC(CC)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)Nc1ccc(C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
To a solution of 6.80 g of 4-(1-ethyl-propylamino)-3-nitro-benzoic acid in 210 ml of dry DMF 1.82 g of HOBT, 7.23 g of EDC and 6.6 ml of DIPEA were added at 0° C. After 30 min 7.24 g of L-leucin-tert.-butylester-hydrochloride and 4.7 ml of DIPEA were added and the reaction was stirred at rt for 4 h. The reaction was then concentrated to about a fifth of its volume and poured into water. It was then extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium carbonate solution and brine, dried over magnesium sulphate and concentrated to yield 11.50 g (100%) of (S)-2-[4-(1-ethyl-propylamino)-3-nitro-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]([N:7]([C@H:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:16]([CH3:32])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[OH-].[Li+].ClCCl.C(=O)(O)[O-].[Na+]>CO.O>[C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]([OH:33])=[O:2])[CH2:15][C@@H:16]1[CH3:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccccc2)c2ccccc21
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: C[C@H]1C[C@@H](N(C(=O)CC(=O)O)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Temperature: 25 °C
Yield: 33.3 %

Procedure:
To a solution of Cis-N-(1-Benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenyl-malonamic acid methyl ester (0.031 g) in a mixture of methanol (1 ml) and water (1 ml), 0.0067 g of lithium hydroxide was added under stirring at room temperature, over night. In order to complete the reaction, 0.0067 g of lithium hydroxide was added and the mixture was stirred over night. Then dichloromethane and an aqueous solution of sodium bicarbonate were added, the organic layer was separated, dried over sodium sulfate, the solvent was removed under reduce pressure to give a solid which was purified by flash chromatography with dichloromethane/methanol (95/5) as eluent to give a solid (0.01 g, 33.3% yield).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1([CH2:18][CH3:19])[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:7][C:6]1=O.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28]N>>[CH2:18]([C:5]1([CH2:4][C:3]([OH:2])=[O:20])[C:6]2[NH:28][C:23]3[C:24](=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[C:7]=2[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:9][CH2:10]1)[CH3:19]
Reactant: C=CCCCCC1CCC(CC)(CC(=O)OC)C(=O)C1
Reactant: Cc1ccccc1NN
Product: C=CCCCCC1CCC(CC)(CC(=O)O)c2[nH]c3c(C)cccc3c21

Procedure:
The title compound was prepared from 1-ethyl-4-(5-hexenyl)-2-oxocyclohexaneacetic acid methyl ester (isomer B) and 2methylphenylhydrazine as described in Example 1, m.p. 111°-112° C.