Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].B1(O)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][O:23]1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:17]1[N:16]=[C:15]([N:9]2[C:10]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB1OCc2ccccc21
Reactant: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3CO)n2)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of the title compound from Example 1 Step A (300 mg, 0.94 mmol), 2,1-benzoxaborol-1(3H)-ol (189 mg, 1.40 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (94 mg, 0.14 mmol), Na2CO3 (1.4 mL, 2.0 M aqueous, 2.8 mmol) and acetonitrile (1.5 mL) in a nitrogen-filled capped vial was stirred at 100° C. for 1.5 h, cooled, concentrated and purified by silica gel flash chromatography (hexanes-EtOAc, 3:1 to 2:1 v/v) to provide the title compound: LCMS 374.1 [M−OH]+; 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.06 (t, J=7.9 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.59-7.41 (m, 5H), 4.51 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C(O[CH:13]=[C:14]([C:20](=[O:23])[CH2:21][CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][CH:13]=[C:14]([C:20](=[O:23])[CH2:21][CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(N)cn1
Reactant: CCOC=C(C(=O)CC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)CC

Procedure:
Ethyl 2-(((6-methoxypyridin-3-yl)amino)methylene)-3-oxopentanoate was prepared with conditions described in Example 99 using 2-methoxy-5-aminopyridine and ethyl 2-(ethoxymethylene)-3-oxopentanoate.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1/[CH:1]=[CH:23]/[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1nc2ccccc2n1-c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccn1
Temperature: 80 °C
Yield: 25.2 %

Procedure:
A stirred mixture of 2-methyl-1-(2-pyridyl)-1H-benzimidazole (0.50 g, 2.39), pyridine-2-carboxaldehyde (0.50 g, 4.67 mmol) and acetic anhydride (5 ml) was heated to 80° C. for 1.5 h and then to reflux for about 6 h. After cooling, the mixture was diluted with water (15 ml), basified with a 10% aqueous solution of sodium hydroxide (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were washed with water (100 ml) and extracted with 2 N hydrochloric acid (3×50 ml). The combined aqueous extracts were basified with a 50% aqueous solution of sodium hydroxide (3×50 ml) and extracted with dichloromethane (4×50 ml). The combined organic extracts were washed consecutively with water (100 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to dryness. Column chromatography (silica gel, 125 g; ethyl acetate) gave 0.18 g of free base (E)-1-(2-pyridyl)-2-[2-(2-pyridyl)ethenyl]-1H-benzimidazole as a brown oil. This product was dissolved into methanol (5 ml), treated with a 10% methanol solution of hydrogen chloride (5 ml) and concentrated to dryness. Recrystallization from 2-propanol afforded 0.15 g (21%) of the titled compound. MW: 371.27; mp: 148.0-155.0° C.; 1H-NMR (DMSO-6) δ: 8.84-8.78 (1H, m), 8.74-8.69 (1H, m), 8.30-8.22 (1H, m), 8.19-8.10 (2H, m), 8.02-7.95 (1H, m), 7.91-7.84 (2H, m), 7.79-7.70 (2H, m), 7.65-7.40 (4H, m).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2=[C:14]([CH3:27])[CH:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-])=O)=[C:10]2[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[CH2:1]([N:8]1[C:9](=[O:28])[C:10]2[C:17]3[C:18]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:24][C:16]=3[CH:15]=[C:14]([CH3:27])[C:11]=2[C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])c2c1C(=O)N(Cc1ccccc1)C2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: Cc1cc2[nH]c3ccccc3c2c2c1C(=O)N(Cc1ccccc1)C2=O
Yield: 46.5 %

Procedure:
30 ml of o-dichlorobenzene was added to a mixture of 2.0 g of N-benzyl-3-methyl-6-(2-nitrophenyl)-phthalimide and 4.2 g of triphenylphosphine. The mixture was refluxed for 8 hours. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=50/1), followed by recrystallization from n-propanol to obtain 850 mg (yield: 47%) of N-benzyl-2-methylcarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC1(C)N([O])C(C)(C)CCC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)nc(Nc2ccc(CO)cc2)c1=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(Br)nc(Nc2ccc(C=O)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (2) (3.1 g; 10 mmol) was dissolved in 150 mL CH2Cl2 at rt under N2. Solid 12 (5.1 g; 20 mmol) was added portion-wise to the stirring reaction, followed by catalytic 2,2,6,6-tetramethyl-1-piperdinyloxy, free radical (TEMPO; 0.23 g; 1.50 mmol). Saturated sodium bicarbonate solution was then added (20 mL) and the reaction allowed to stir overnight at rt under N2. The resulting light orange solid was filtered off and washed repeatedly with CH2Cl2 and diethyl ether until the extractions ran clear and colorless. After drying, 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzaldehyde (3) was obtained in nearly quantitative yields (3.1 g) and was carried directly on to the next reaction. MS 308.01 & 310.01 (M+H)
Reaction SMILES: [CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:4])[O-:3].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:3])[O:4][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])P(C)(=O)[O-]
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COP(C)(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
In the same way, P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate acid and ethyl bromoacetate are reacted together to give ethoxycarbonylmethyl P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[Br:27][C:28]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][C:28]=4[Br:27])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Br
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)c1ccc([N+](=O)[O-])cc1Br)c1ccnc2cc3c(cc12)OCO3

Procedure:
To a solution of compound 7 (259 mg, 1.0 mmol) and triethylamine (0.5 mL) in dry CH2Cl2 (20 mL) was added a solution of 2-bromo-4-nitrobenzoic acid chloride in 20 mL of CH2Cl2 (which was prepared by refluxing of 295 mg, 1.2 mmol of 2-bromo-4-nitrobenzoic acid in 10 mL of thionyl chloride for 4 h). The reaction mixture was heated to reflux for 6 h. The reaction mixture was allowed to cool and was then washed with saturated NaHCO3 solution, water and brine and dried over anhydrous Na2SO4. The solvent was then removed in vacuo to give a yellow solid; yield 345 mg (70.8%); mp 111–112° C.; 1H NMR (CDCl3) δ (2.29, S, 6H), 2.60 (t, 2H, J=6.2), 3.62–3.72 (m, 1H), 4.49–4.62 (m, 1H), 6.19 (d, 2H, J=5.6), 7.12 (d, 1H, J=8.2), 7.37 (s, 3H), 7.75 (d, 1H, J=8) 8.26 (s, 1H), 8.5 (d, 1H, J=4.6); 13C NMR(CDCl3) δ 45.4, 46.6, 56.4, 97.8, 102.4, 106.7, 119.5, 120.6, 121.7, 122.7, 127.6, 128.1, 143.6, 144.4, 147.9, 148.2, 148.5, 149.5, 151.4, 166.8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[C:9]([NH2:23])[O:8]2)[CH:2]=1.[OH-].[Na+].[CH3:26]OS(OC)(=O)=O>C(Cl)Cl.O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[C:9]([NH:23][CH3:26])[O:8]2)[CH:2]=1
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2cccnc2)O1
Reactant: COS(=O)(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2cccnc2)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Two (2) grams of 2-(pyrid-3-yl)-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran was dissolved in 50 ml of methylene chloride at room temperature. 0.24 g of sodium hydroxide, dissolved in the minimum amount of water needed to dissolve the sodium hydroxide, and 0.46 g of benzyltrimethylammonium chloride was added. Then a solution containing 0.79 g of dimethylsulfate in about 10 ml of methylene chloride was slowly added and the mixture stirred for two days at room temperature. The mixture was then washed with water, dried over magnesium sulfate and evaporatyed to a solid residue. The residue was triturated with 30% vol. ethyl acetate: 70% petroleum ether and filtered.
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[O:13][C:8]=2[CH:7]=1)=[O:5])C.C(OC(=O)C(CC)CCN1C(=S)N2C3C=C(C4C=CC(Cl)=CC=4)OC=3C=C2C1=O)C.[CH2:51]([O:53][P:54]([CH2:59][CH2:60][CH2:61][N:62]=[C:63]=[S:64])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52].C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:51]([O:53][P:54]([CH2:59][CH2:60][CH2:61][N:62]1[C:63](=[S:64])[N:10]2[C:9]3[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=4)[O:13][C:8]=3[CH:7]=[C:6]2[C:4]1=[O:5])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]
Reactant: CCOC(=O)c1cc2oc(-c3ccc(Cl)cc3)cc2[nH]1
Reactant: CCOP(=O)(CCCN=C=S)OCC
Agent: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOP(=O)(CCCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S)OCC
Temperature: 110 °C
Yield: 59.4 %

Procedure:
2-(4-Chloro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (60.97 mg, 0.21 mmol), prepared by the procedure described above (see, Compound 4), (3-isothiocyanopropyl)phosphonic acid diethyl ester (500 mg, 2.1 mmol) and a fine powder of anhydrous K2CO3 (27.6 mg, 0.2 mmol) were mixed together in a sealed tube, provided with a magnetic stirrer, and the mixture was heated at 110° C. for 2 hours. The mixture was then cooled to room temperature, ethanol (2 ml) was added, and the formed precipitate was filtered. The compound was recrystallized from ethanol to give of Compound 27 (60 mg, 60% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.Cl.[CH3:10][O:11][CH:12]1[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:15][CH:12]([O:11][CH3:10])[CH2:13]2)=[N:6][CH:7]=1
Reactant: COC1CNC1
Reactant: Fc1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC1CN(c2ccc(Br)cn2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
5-Bromo-2-fluoropyridine (1.7 g) was mixed with N,N-dimethylacetamide (5 ml), and 3-methoxyazetidine hydrochloride (335 mg) and potassium carbonate (1.5 g) were added thereto, followed by stirring at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 5-bromo-2-(3-methoxyazetidin-1-yl)pyridine (581 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18](S(C1C=CC(C)=CC=1)(=O)=O)[C:17]1[CH:16]=[N:15][C:14]([CH:32]([OH:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:13]([CH2:40][O:41][CH3:42])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[H-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([CH:32]([OH:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:13]([CH2:40][O:41][CH3:42])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1c(C(O)c2ccccc2)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: COCc1c(C(O)c2ccccc2)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Yield: 95.9 %

Procedure:
300 mg of 6-benzyloxy-3-(1-hydroxy-1-phenylmethyl)4methoxymethyl-9-(4-methylphenylsulfonyl)-beta-carboline was added a sodium methylate solution of 50 mg of 80% sodium hydride and 30 ml of absolute ethanol and refluxed for 2 hours under argon. After distilling off the solvent, the residue was taken up in ethyl acetate and washed with saturated sodium chloride solution. After column chromatography on silica gel in the system of dichloromethane/ethanol 12:1, 211 mg of the title compound was obtained after recrystallization from ethyl acetate/petroleum ether from the ethyl acetate phase dried on magnesium sulfate and concentrated by evaporation, melting point 190°-191° C.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29](Cl)=[O:30])=[CH:23][CH:22]=1.C(OCC)(=O)C>O1CCOCC1.O>[CH2:27]([O:28][C:29]([NH:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)=[O:30])[C:24]1[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (4.40 g, 21.76 mmol) and Na2CO3 (2.77 g, 26.11 mmol) in dioxane (50 mL) and water (50 mL) was added Cbz-Cl (3.87 mL, 26.11 mmol) at 0° C. The reaction mixture was warmed to ambient temperature and stirred at ambient temperature for 3 hours. Ethyl acetate (50 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give (3R,4R)-tert-butyl 3-(benzyloxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate (4.91 g, 67.1%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][N:14]=2)CC1)=[O:8].O.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:25][CH:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:27]2)=[C:6]([CH:23]=1)[C:7]([NH:9][CH2:10][C:13]1[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(F)c4)C3)CC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(CNC(=O)c2cc(Cl)cnc2N2CC(Oc3cccc(F)c3)C2)nc1
Temperature: 70 °C
Yield: 92.4 %

Procedure:
To a solution of methyl 6-((5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinamido)methyl)nicotinate (D159) (22 mg, 0.045 mmol) in a mixture 1-4dioxane/water (1.5 ml/0.5 ml), lithium hydroxide hydrate (2.8 mg, 0.067 mmol) was added. The reaction mixture was heated to 70° C. for 1 h. After solvent evaporation the residue was taken in water (10 ml) and 1M HCl (10 ml) and extracted with ethylacetate (2×20 ml). Collected aorganics after solvent evaporation afforded the title compound (E24) (19 mg)
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[C:60]([C:64]1[CH:72]=[CH:71][C:67]([C:68](Cl)=[O:69])=[CH:66][CH:65]=1)([CH3:63])([CH3:62])[CH3:61]>>[C:60]([C:64]1[CH:65]=[CH:66][C:67]([C:68]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C:51]5([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:69])=[CH:71][CH:72]=1)([CH3:63])([CH3:61])[CH3:62]
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCCC1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C(C)(C)C)cc5)cc4)cc3C2=O)CCCC1
Yield: 79 %

Procedure:
The compound of example 530 was prepared analogous to compound of example 97 by reaction of compound of example 527 with 4-(t-butyl)benzoyl chloride.
Reaction SMILES: [P:1]([O-:38])([O:34][CH2:35][CH2:36]Br)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2].[CH3:39][N:40]([CH3:42])[CH3:41]>>[P:1]([O-:38])([O:34][CH2:35][CH2:36][N+:40]([CH3:42])([CH3:41])[CH3:39])([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)Oc1ccon1
Reactant: CN(C)C
Product: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[N+](C)(C)C)Oc1ccon1

Procedure:
11(b) 0.800 g of (2RS)-3-(N-heptadecylcarbamoyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in step (a) above] was reacted with trimethylamine in a similar manner to that described in Example 1(b), to give 0.640 g of the title compound as viscous oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[CH:3]=O.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1.ClC(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[CH:3]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC1=C(CCC(C)C=O)C(C)(C)CCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)OCC

Procedure:
Under the conditions described in example 1, titanium(IV) chloride (91 g, 0.5 mol), 2-methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butanal 4 (50 g, 0.24 mol) and diethyl malonate (39.7 g, 0.24 mol) in tetrahydrofuran and tetrachloromethane are reacted which each other to give after work-up and short-path-distillation 70.1 g (83%) of 3b. Analytical data: 1H-NMR (400 MHz, CDCl3): δ 0.97 (s, 6 H), 1.1 (d, 3 H), 1.25-1.6 (6 H), 1.3 (2t, 6 H), 1.58 (s, 3 H), 1.8-2.0 (2 H), 2.55 (m, 1 H), 4.15-4.35 (2q, 4 H), 6.8 (d, 1 H) ppm. 13C-NMR (400 MHz, CDCl3): δ 14.0 (q), 14.15 (q), 19.5 (t), 19.6 (q), 19.8 (q), 26.5 (t), 28.5 (q), 32.7 (t), 34.85 (s), 35.6 (d), 36.9 (t), 39.8 (t), 61.1 (t), 61.15 (t), 127.0 (s), 127.5 (s), 136.9 (s), 153.9 (d), 164.0 (s), 165.7 (s). MS (EI): m/z (%) 350 (M+, 4), 335 ([M-15]+, 3), 305 (4), 289 (5), 259 (9), 243 (11), 215 (8), 200 (98), 190 (18), 187 (11), 175 (16), 173 (27), 167 (18), 154 (100), 135 (30), 123 (42), 122 (30), 121 (39), 109 (19), 108 (60), 107 (32), 105 (19), 95 (52), 93 (34), 91 (25), 81 (40), 79 (30), 77 (15), 69 (21), 67 (26), 55 (36), 41 (32), 29 (28). JR (film): 2950 (m), 2960 (m), 2930 (m), 2862 (m), 1725 (s), 1645 (w), 1455 (m), 1375 (m), 1325 (w), 1250 (s), 1222 (s), 1205 (s), 1180 (m), 1170 (m), 1100 (m), 1050 (m), 1030 (m), 950 (w), 865 (w), 800 (w), 765 (w).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[CH3:34][NH:35][C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36](=[O:44])[NH:35][CH3:34])[CH2:43][CH2:42]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CNC(=O)CN1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added N-methyl-2-(piperazin-1-yl)acetamide hydrochloride (125 mg, 0.65 mmol), HATU (185 mg, 0.49 mmol), DIEA (126 mg, 0.97 mmol). The resulting solution was stirred at room temperature for 12 h and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 8% MeOH in DCM. The crude product (180 mg) was purified by Prep-HPLC with the following conditions (3#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mM NH4CO3 and MeCN (26.0% MeCN up to 40.0% in 8 min); Detector, 254/220. This resulted in 73.9 mg (38%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(methylcarbamoyl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 20) [M+H]+=602.2, RT=3.66 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.75 (q, 1H, J=4.8 Hz), 7.63 (dd, 1H, J=2.6, 8.6 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 3.54 (t, 4H, J=5.0 Hz), 2.95 (s, 2H), 2.63 (d, 3H, J=4.8 Hz), 2.48-2.45 (m, 2H), 2.44-2.41 (m, 2H).