Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4](N(C)C)OC(C)(C)C)[CH3:3].[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH3:37])[CH:32]([NH:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:31]2=[O:47])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C.C1CCCCC1>[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH:37]=[CH:1][N:2]([CH3:4])[CH3:3])[CH:32]([NH:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:31]2=[O:47])=[O:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)c3ccccc3)C2SC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)c3ccccc3)C2SC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 38.9 %

Procedure:
bis-Dimethylamino-tert.-butoxymethane (10 g) is added, under a dry nitrogen atmosphere, to a solution of 2-benzhydryloxycarbonyl-7-benzoylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (24 g) in anhydrous N,N-dimethylformamide (100 cc). The reaction mixture is stirred at 25° C. for 23 hours and is then poured into a mixture of ethyl acetate (300 cc) and an aqueous saturated sodium chloride solution (700 cc). The aqueous phase is decanted and extracted with ethyl acetate (250 cc). The organic phases are combined, washed with 1 N aqueous hydrochloric acid (250 cc), with distilled water (500 cc) and with a saturated aqueous sodium chloride solution (300 cc) and then dried over magnesium sulphate in the presence of decolorising charcoal, and filtered. The solvent is evaporated under reduced pressure (20 mm Hg) at 30° C. The residue is dissolved in methylene chloride (200 cc) and fixed to silica (50 g). The powder obtained is placed in a column (height 60 cm, diameter 5 cm) containing silica gel (415 g) in a 95:5 (by volume) mixture of cyclohexane and ethyl acetate. Elution is carried out with the following mixtures of cyclohexane and ethyl acetate: 95:5 (by volume) (5 liters), 90:10 (by volume) (5 liters), 80:20 (by volume) (5 liters), 70:30 (by volume) (7.5 liters) (so as to elute the impurities) and 60:40 (by volume) (8 liters) the latter being collected and concentrated to dryness. 2-Benzhydryloxycarbonyl-7-benzoylamino-3-(2-dimethylamino-vinyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2 -ene (E-form) (10.4 g) is obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1I)[CH3:2].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1)CCC.[F-].[Cs+]>C(#N)C.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.[Cu](I)I>[N:24]1[CH:23]=[CH:22][C:27]([C:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[O:16])=[CH:26][N:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1I
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1-c1ccnnc1
Temperature: 45 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a solution of 2-iodo-4-trifluoromethylbenzoic acid ethyl ester (200 mg, 0.581 mmol) in acetonitrile (5 mL) was added 4-(tributylstannyl)pyridazine (214 mg, 0.581 mmol) and caesium fluoride (176 mg, 1.16 mmol). The solution was sparged with nitrogen before the addition of tetrakis(triphenylphosphine)palladium (0) (26 mg, 0.023 mmol) and copper iodide (22 mg, 0.116 mmol). The reaction mixture was sparged with nitrogen then heated at 45° C. for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and filtered through Celite™. An aqueous solution of potassium fluoride was added and the reaction mixture was stirred for 16 hours. The organic layer was separated, washed with water, followed by a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The material was purified by column chromatography (100-200 silica, eluting with 60% ethyl acetate in heptane). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a solid (140 mg).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(S([S:21][CH2:22][CH:23]([N:35]([CH3:37])[CH3:36])[CH2:24][S:25]S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:25][CH2:24][CH:23]([N:35]([CH3:37])[CH3:36])[CH2:22][S:21]1)=[O:8])[CH3:11]
Reactant: CN(C)C(CSS(=O)(=O)c1ccccc1)CSS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)OCC)SCC(N(C)C)CS1
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To 20 ml of chloroform were added 1.6 g (0.01 mole) of diethyl malonate and 4.3 g (0.01 mole) of 1,3-bis(benzenesulfonylthio)-2-(N,N-dimethylamino)propane, and then 2.1 g (0.02 mole) of triethylamine was added thereto at room temperature. After completion of addition, the reaction was allowed to proceed at 40° C. for 4 hours. The reaction mixture was washed with two 20-ml portions of water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was heated in 20 ml of ether-hexane (1:1) for dissolution and the solution was allowed to stand in the cold overnight. The resulting crystalline precipitate was collected by filtration to give 2.7 g (90%) of 2,2-diethoxycarbonyl-5-(N,N-dimethylamino)-1,3-dithiane as light-yellow crystals melting at 38°-39° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:18]1([N:15]2[CH2:16][CH2:17][CH:12]([N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:11])[CH3:10])[CH2:13][CH2:14]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCCCC1
Reactant: CC(=O)N(c1ccc(F)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)N(c1ccc(F)cc1)C1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(4-fluoro-phenyl)-N-piperidin-4-yl-acetamide (60 mg; 0.25 mmol; 1 eq.), see Example 6 for deprotection procedure, and cyclohexanone (29 mg; 0.30 mmol; 1.2 eq.) were dissolved in DCE (2 mL). NaBH(OAc)3 (108 mg; 0.51 mmol; 2 eq.) was added, and the reaction was stirred at room temperature for 72 hours and then quenched with 1N NaOH (5 mL). DCM (5 mL) was then added and the layers were separated. The aqueous layer was washed with DCM (10 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using reversed-phase HPLC (2-99% CH3CN/H2O gradient with 0.05% TFA). LC/MS M/Z 319.2, Retention time=1.88 minutes; 10-99% CH3CN/H2O gradient with 0.05% TFA.
Reaction SMILES: [Cr](O)(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15]([OH:24])[C:16]([CH3:23])([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH3:17])=[CH:9][CH:8]=1>O.C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15](=[O:24])[C:16]([CH3:17])([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH3:23])=[CH:11][CH:12]=1
Reactant: CC(C)(C(O)CCc1ccc(Cl)cc1)n1cccn1
Agent: O=[Cr](=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C(=O)CCc1ccc(Cl)cc1)n1cccn1
Temperature: 25 °C
Reaction time: 25 h
Yield: 93.9 %

Procedure:
A solution of 6.4 g (0.064 mol) of chromic acid in 5 ml of water and 20 ml of glacial acetic acid is added dropwise at 5° C. to a solution of 23.5 g (0.085 mol) of 5-(4-chlorophenyl)-2-methyl-2-(pyrazol-1-yl) -pentan-3-ol in 60 ml of glacial acetic acid in the course of one hour. The mixture is subsequently stirred for a further 25 hours at room temperature. The mixture is stirred into 2,000 ml of water and extracted five times with 200 ml of methylene chloride each time, and the solvent is removed by distillation. 22.1 g (94% of theory) of 5-(4-chloro-phenyl)-2-methyl-2-(pyrazol-1-yl)-pentan-3-one of diffraction index n23D =1.5278 are obtained. ##STR23##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[S:12]([OH:14])=[O:13].O.[OH-].[Na+].[CH3:18]I>CO>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:12]([CH3:18])(=[O:14])=[O:13])=[CH:4][C:5]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc(S(=O)O)c(Cl)cc1Cl
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Yield: 56 %

Procedure:
The product of Step A is placed in a three-liter flask to which is added water (300 ml.), methanol (500 ml.) sufficient 10N sodium hydroxide to attain a pH of 9 and methyl iodide (520 g.; 3.66 moles). The reaction mixture is refluxed for 36 hours with the occasional addition of 10N sodium hydroxide to maintain pH 9. The alcohol is distilled at reduced pressure and the reaction solution is acidified with hydrochloric acid. The product is filtered, washed with water, dried and recrystallized from ethanol (800 ml.) to give 150 g. (yield 56%) 2,4-dichloro-5-methylsulfonylbenzoic acid, m.p. 210°-211° C.
Reaction SMILES: [CH:1]1([C:7]([N:9]([CH3:37])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:25][C:26]3[S:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].O>C1COCC1.CO.O>[CH:1]1([C:7]([N:9]([CH3:37])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:25][C:26]3[S:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](Cc1ccc(OCCN(C)C(=O)C2CCCCC2)cc1)Nc1nc(-c2ccccc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(CCOc1ccc(C[C@H](Nc2nc(-c3ccccc3)cs2)C(=O)O)cc1)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The crude product from Step B was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCL, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[CH3:10]C([N-]C(C)C)C.[Li]CCCC.IC.C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: Clc1cncc(Cl)c1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(Cl)cncc1Cl
Reaction time: 0.08 h
Yield: 53 %

Procedure:
3,5-Dichloropyridine (2.04 g, 13.5 mmol) in THF (5 ml) was added dropwise to a solution of LDA [prepared from diisopropylamine (1.9 ml, 13.5 mmol) and n -BuLi (1.6M; 8.4 ml, 13.5 mmol)] in THF (25 ml) at -70° C. After stirring at this temperature for 5 min, iodomethane (0.85 ml, 13.5 mmol) was added and the reaction mixture stirred for a further 1.5h at -70° C. Saturated NaHCO3 (20 ml) and CH2Cl2 (20 ml) were added, the organic phase separated, dried (MgSO4), and concentrated in vacuo. The residue was subjected to chromatography (SiO2 ; Et2O/hexane, 1.:3) to afford the title compound (1.16 g) as a pale yellow solid. δH (CDCl3) 2.46 (3H, s, Me), and 8.36 (2H, s, pyridine H2, H6).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:9])[CH3:8])[CH2:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:9])[CH3:8])[CH2:2]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)N[C@@H]1CCNC1
Product: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
(R)-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene by method C. This resulted in the product with the molecular weight of 249.27 (C12H15N3O3); MS (ESI): 250 (M+H+).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=1)=[O:19]
Reactant: CON(C)C(=O)C=Cc1cccc(Cl)c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(3-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (14 g) as an oil.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3C[C@@H](C)N(CC4C=CC=CN=4)[C@@H](C)C3)=CC=2N=1.[CH3:33][C@H:34]1[CH2:39][NH:38][CH2:37][C@@H:36]([CH3:40])[N:35]1[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1.C([O:52][C:53](N1C[C@H](C)N[C@H](C)C1)=[O:54])(C)(C)C.Br.BrCC1C=CC=CN=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[CH3:33][C@@H:34]1[N:35]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[C@H:36]([CH3:40])[CH2:37][N:38]([C:53]([OH:54])=[O:52])[CH2:39]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: C[C@@H]1CNC[C@H](C)N1Cc1ccccn1
Agent: Br
Agent: BrCc1ccccn1
Agent: C[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C[C@H](C)N1Cc1ccccn1
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)O)C[C@H](C)N1Cc1ccccn1

Procedure:
Via 2-Chloro-6-((3S,5R)-3,5-dimethyl-4-pyridin-2-ylmethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared from (2S,6R)-2,6-dimethyl-1-pyridin-2-ylmethyl-piperazine. Amine preparation: (3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (845 mg), 2-(bromomethyl)-pyridine hydrobromide (1 g) and potassium carbonate (1.15 g) was heated to reflux in MeCN (10 mL). After heating for 24 h the reaction mixture was diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield (3S,5R)-3,5-dimethyl-4-pyridin-2-ylmethyl-piperazine-1-carboxylic acid tent-butyl ester (867 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH2:1](Br)[C:2]#C.[CH2:5]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](=[O:28])(=[O:27])[NH2:26])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[CH:6]=[CH2:7]>>[CH2:1]([O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:16]([S:25](=[O:28])(=[O:27])[NH2:26])[C:17]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([NH:8][CH2:5][C:6]#[CH:7])[CH:10]=1)[CH3:2]
Reactant: C#CCBr
Reactant: C=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: C#CCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
By substituting propargyl bromide (4.8 g) for the allyl bromide of Example 58 A and extending the reaction time to 48 hours, ethyl-4-phenoxy-3-propargylamino-5-sulphamyl-benzoate was obtained with a melting point of 189°-190°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:34]([C:33]1[CH:32]=[C:31]([C:29](=[O:30])[CH2:28][C:27]([NH:1][C:2]2[CH:3]=[C:4]([N:11]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]([C:22]#[N:23])=[CH:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[O:26])[CH:38]=[CH:37][CH:36]=1)#[N:35]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: N#Cc1cn(-c2ccc([N+](=O)[O-])c(N)c2)cc1-c1ccccc1
Product: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cc(C#N)c(-c4ccccc4)c3)ccc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared from 1-(3-amino-4-nitro-phenyl)-4-phenyl-1H-pyrrole-3-carbonitrile (Example E3) (254 mg, 0.835 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (210 mg, 0.919 mmol) according to the general procedure M. Obtained as an orange solid (287 mg).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH:11]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:15][CH:14]3[C:12]2([C:27](Cl)=[O:28])[CH2:13]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.CC(C)=O>[C:5]1([CH:11]2[N:16]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH2:15][CH:14]3[C:12]2([C:27]([N:1]=[N+:2]=[N-:3])=[O:28])[CH2:13]3)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)Cl)C2c2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)N=[N+]=[N-])C2c2ccccc2)cc1
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred solution of sodium azide (5.63 g, 86.62 mmol) in 17 mL of water was added in a dropwise fashion to a solution of racemic 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (5.0 g, 13.3 mmol) (Intermediate 3) in 30 mL of acetone. 3 mL of water was then added to the reaction and the reaction mixture was stirred for 16 hours. The acetone was removed at reduced pressure and the reaction diluted with both methylene chloride and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl azide (5.1 g, 100% crude yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC.[BH4-].[Na+]>C1COCC1.C(=O)(O)[O-].[Na+].CO>[F:36][C:33]1[CH:34]=[CH:35][C:23]2[N:22]=[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]3[CH2:11][C@@H:10]([CH2:37][OH:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13]3)=[O:20])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]=2[CH:32]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (274 mg) and 4-methylmorpholine (66 μl) in THF (5 ml) was added dropwise ethyl chlorocarbonate (57 μl) at 0° C., and the mixture was stirred at the same temperature for 1 hr. Sodium borohydride (57 mg) and methanol (1 ml) were added to the reaction mixture, and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (182 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29](O)=[O:30])[CH:28]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][NH2:41])=[CH:36][C:35]=1[CH3:42].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.CO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29](=[O:30])[NH:41][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[C:35]([CH3:42])[CH:36]=3)[CH:28]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1N1CCC(C)(C)CC1
Reactant: Cc1cc(CN)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CNC(=O)c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N4CCC(C)(C)CC4)n3n2)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
To a mixture of (S)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (50 mg, 0.112 mmol) and (4-fluoro-3-methylphenyl)methanamine (31.2 mg, 0.224 mmol) in DMF (2 mL) was added DIEA (0.098 mL, 0.560 mmol), HATU (85 mg, 0.224 mmol) and DMAP (2.74 mg, 0.022 mmol) and the resulting mixture was stirred at room temp for 16 h. At this point LCMS indicated completion of reaction. Water was then added and the mixture was extracted with ethyl acetate (25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then treated with 1N NaOH (0.336 mL, 0.336 mmol) in MeOH (2.000 mL) at 60° C. for 5 h. The mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-2-((4-fluoro-3-methylbenzyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (26.2 mg, 0.046 mmol, 41.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.76 (t, J=6.3 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.23-7.17 (m, 1H), 7.10 (t, J=9.0 Hz, 1H), 6.82 (s, 1H), 5.43 (s, 1H), 4.48 (d, J=6.1 Hz, 2H), 3.32-3.39 (m, 4H), 2.23 (s, 3H), 1.92 (s, 3H), 1.60 (br. s., 2H), 1.46 (br. s., 2H), 1.14 (s, 9H), 1.07 (br. s., 6H). LCMS (M+H)=540.5.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f43) and commercially available propionyl chloride the title compound is obtained as colorless solid.