Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl[C:30]1[N:35]=[C:34]([NH:36][C:37]([CH3:44])([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39])[CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:44][C:37]([NH:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:28])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH:11]=2)[N:35]=1)([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CCC(C)(Nc1ccnc(Cl)n1)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCC(C)(Nc1ccnc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)n1)C(=O)OC
Temperature: 90 °C
Yield: 161.8 %

Procedure:
A 500 mL pressure vessel was charged with 80 mL DME, 1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (4.4 g, 11.05 mmol), methyl 2-((2-chloropyrimidin-4-yl)amino)-2-methylbutanoate, (2.44 g, 10.05 mmol), sodium carbonate (10 mL of 2M aq solution, 20 mmol) and degassed the mixture with a nitrogen stream for 30 min. Then, Pd(dppf)Cl2 was added, the flask sealed and heated to 90° C. for 15 hours. The mixture was cooled and filtered through Florisil. Evaporation under vacuum gave 7.8 g of a brown residue which was purified by flash chromatography, (0-80% ethyl acetate-hexane affording 3.9 g (81%) methyl 2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)butanoate. 1H NMR (CDCl3) 8.83 (dd, 1H), 8.52 (s, 1H), 8.44 (dd, 1H), 7.28 (dd, 4H), 6.27 (d, 1H), 5.29 (s, 1H), 3.74 (d, 3H), 2.38 (s, 3H), 2.34-2.15 (m, 1H), 2.18-2.00 (m, 2H), 1.98 (s, 2H), 1.74 (s, 3H), 1.34-1.17 (m, 15H), 1.03 (m, 3H). m/e m+1 480.25
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[NH2:24][CH2:25][CH2:26][S:27]([O-:29])=[O:28].[Na+].OC1C=CC(NC(=O)C)=CC=1.O>C(#N)C>[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][C:1]([NH:24][CH2:25][CH2:26][S:27]([OH:29])=[O:28])=[O:23])=[CH:8][CH:7]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: NCCS(=O)[O-]
Agent: CC(=O)Nc1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccc(OC(=O)NCCS(=O)O)cc1

Procedure:
Title compound 11a was prepared according to the General Method for the Reaction of Alkali Metal Salts of Amino Acid Derivatives with 4-Acetamidophenyl 4-Nitrophenyl Carbonate (3). A solution of 410 mg (3.20 mmol) of sodium 2-aminoethanesulfinate (5) in approximately one (1) mL of degassed water was reacted with a solution of 4-acetamidophenyl 4-nitrophenyl carbonate (3) (1.01 g, 3.19 mmol) in 10 mL of acetonitrile (MeCN). After work-up procedures, the aqueous layer was lyophilized off to afford 910 mg (˜quantitative yield) of the crude 2-((4-acetamidophenoxy)carbonylamino)ethanesulfinic acid (11a) which was used directly and without further isolation or purification procedures in the next step. The material thus obtained was contaminated with some sodium chloride (NaCl) and/or other sodium salts. 1H NMR (300 MHz, D2O): δ 7.22 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 3.31 (t, J=6.6 Hz, 2H), 2.42 (t, J=6.6 Hz, 2H), 1.96 (s, 3H). LC/MS (ESI): m/z=287.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:41]2[C:40](=[O:42])[N:39]([CH3:43])[C:38](=[O:44])[N:37]([CH3:45])[C:36]=2[N:35]=[CH:34]1)OC(SC)=S)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH:9]1[CH2:21][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:41]2[C:40](=[O:42])[N:39]([CH3:43])[C:38](=[O:44])[N:37]([CH3:45])[C:36]=2[N:35]=[CH:34]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSC(=S)OC(c1ccccc1-n1cnc2c1c(=O)n(C)c(=O)n2C)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cn1c(=O)c2c(ncn2-c2ccccc2CC2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)n(C)c1=O
Yield: 83.7 %

Procedure:
2-[1-[2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-yl)-phenyl]-1-methylsulfanylthiocarbonyloxymethyl]piperazine-1,4-dicarboxylic acid di-tert-butyl ester (low polarity) (0.175 g), tributyltin hydride (0.25 g), and 2,2′-azobis(isobutyronitrile) (0.010 g) were dissolved in toluene (5 ml) under nitrogen atmosphere, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled and the solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to give 0.123 g of the title compound from the elution fraction of hexane-ethyl acetate (1:1).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:37][CH2:38][C:39]1([C:45]([O:47][CH3:48])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:9]([O:8][C:6]([NH:1][CH2:2][C:3]([N:42]1[CH2:43][CH2:44][C:39]([CH2:38][OH:37])([C:45]([O:47][CH3:48])=[O:46])[CH2:40][CH2:41]1)=[O:5])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)C1(CO)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(CO)CCN(C(=O)CNC(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of Boc-Gly-OH (331 mg, 1.89 mmol, 1.1 equiv.) in DMF (1 mL) was added HBTU (718 mg, 1.89 mmol, 1.1 equiv.), followed by addition of methyl 4-(hydroxymethyl)piperidine-4-carboxylate (1.72 mmol, 1 equiv.) and DIEA (749 μL, 4.30 mmol, 2.5 equiv.) at rt. The reaction mixture was stirred for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed by saturated NaHCO3, water and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by column chromatography to give methyl 1-(2-(tert-butoxycarbonylamino)acetyl)-4-(hydroxymethyl)piperidine-4-carboxylate (560 mg, 98%, two steps). LRMS (M-Boc+H+) m/z 231.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=4)=[C:11]3[C:10]([CH3:27])=[N:9]2)=[CH:5][CH:4]=1.CCO>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[N:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=4)=[C:11]3[C:10]([CH3:27])=[N:9]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc([N+](=O)[O-])cn4)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cn4)ccnc32)cc1
Temperature: 80 °C
Yield: 69.4 %

Procedure:
A 25 mL round-bottomed flask was charged with 1-(4-methoxybenzyl)-3-methyl-4-(5-nitropyridin-2-yloxy)-1H-pyrazolo[3,4-b]pyridine (1.25 g, 3.19 mmol) and EtOH (10 mL). SnCl2 dihydrate (3.60 g, 16.0 mmol) was added under nitrogen and the reaction mixture was heated to 80° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with Na2CO3 (100 mL, 2N) and extracted with chloroform (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to a dark oil. The crude material was purified on a Biotage 40S column, eluting with EtOAc, to provide the product (800 mg, 65%) as a green oil. 1H NMR (CDCl3, 400 MHz) δ 8.31 (d, J=5.1 Hz, 1H), 7.82 (m, 1H), 7.29 (m, 2H), 7.18 (m, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.82 (m, 2H), 6.40 (d, J=5.5 Hz, 1H), 5.56 (s, 2H), 3.76 (m, 5H), 2.63 (s, 3H). LRMS (APCI pos) m/e 362 (M+1).
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[C:6]([CH3:17])=[N:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]=1[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C(O)(C)C.O>[CH3:17][C:6]1[C:5]([CH2:4][CH:3]=[O:2])=[C:9]([CH3:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COC=Cc1c(C)nn(-c2ccccc2)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cc1nn(-c2ccccc2)c(C)c1CC=O
Temperature: 60 °C
Yield: 60.5 %

Procedure:
To a stirred solution of 4-(2-methoxy-vinyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (7.09 g, 31.1 mmol) in 100 mL isopropanol-water (1:1 v/v) was added p-toluenesulfonic acid monohydrate (1.5 g, 7.76 mmol). After the reaction was heated at 60° C. for 16 h, 1.9 mL concentrated hydrochloric acid was added and the reaction mixture was heated at 60° C. for 20 h. The organic solvent was removed in vacuo and the remaining aqueous suspension was neutralized with an aqueous sodium bicarbonate solution and extracted several times with a dichloromethane-ethyl acetate mixture. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to produce a residue, which was purified via silica gel column chromatography (0-50% ethyl acetate in heptane) to give the title compound as a yellow solid (4.02 g, 18.8 mmol, 60% yield).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[C:15]([CH2:17][CH2:18][CH3:19])[CH:14]=[C:13]([F:20])[C:12]=1[CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH2:25][CH2:24]1>C(COC)OC.FC(F)(F)S(O)(=O)=O>[F:7][C:32]1[CH2:33][CH2:34][CH:29]([C@H:26]2[CH2:27][CH2:28][C@H:23]([CH2:22][CH2:21][C:12]3[C:11]([F:10])=[CH:16][C:15]([CH2:17][CH2:18][CH3:19])=[CH:14][C:13]=3[F:20])[CH2:24][CH2:25]2)[CH2:30][CH:31]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCc1cc(F)c(CC[C@H]2CC[C@H](C3CCC(=O)CC3)CC2)c(F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COCCOC
Product: CCCc1cc(F)c(CC[C@H]2CC[C@H](C3CC=C(F)CC3)CC2)c(F)c1

Procedure:
1.1 ml of diethylaminosulphur trifluoride (DAST) are added dropwise in 3 portions over 60 hours to a solution of 1.7 g of 4-{trans-4-[2-(2,6-difluoro-4-propylphenyl)ethyl]cyclohexyl}cyclohexanone in 30 ml of dimethoxyethane and 0.1 ml of trifluoro-methanesulphonic acid. The reaction solution is subsequently partitioned between sodium carbonate solution/ether. The organic phase is washed twice with water and the aqueous phases are individually extracted twice with ether. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated completely. The crude product obtained is chromatographed over silica gel and gives 1-fluoro-4-{trans-4-[2-(2,6-difluoro-4-propylphenyl)ethyl]cyclohexyl }cyclohex-1-ene.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:17][CH:18]=[C:19]([CH2:21]O)[N:20]=3)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:21][C:19]1[N:20]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:11][CH:12]=2)[O:17][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1coc(-c2ccc(-n3cnc4ccccc43)cc2)n1
Solvent: ClCCl
Product: ClCc1coc(-c2ccc(-n3cnc4ccccc43)cc2)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of {2-[4-(1H-benzimidazol-1-yl)phenyl]-1,3-oxazol-4-yl}methanol (0.35 g, 1.2 mmol) in CH2Cl2 was cooled to 0° C., treated with a solution of thionyl chloride (0.37 g, 3.0 mmol) in CH2Cl2, stirred at 0° C. for 3 h and concentrated in vacuo. The resultant residue was partitioned between CH2Cl2 and water. The organic phase was separated, washed sequentially with water and brine, dried over Na2SO4 and evaporated to dryness under reduced pressure to afford the title product, 1HNMR (CDCl3, 400 MHz): 8.25 (d, J=8.4 Hz, 2H), 8.17 (s, 2H), 7.67 (d, J=8.0 Hz, 1H), 7.60 (d, J=5.6 Hz, 1H), 7.36-7.38 (m, 3H), 7.26 (s, 1H), 4.61 (s, 2H). LCMS (ESI+) 310 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=2)[O:24][C:25]=1[CH3:26].FC1C=CC(C=O)=CC=1C.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Agent: Cc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 144 a], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole (prepared from 4-fluoro-3-methyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2>>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[C:25]2=[CH:16][C:13]1[NH:12][C:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]3[CH2:19][CH2:20][CH2:2][CH2:1]3)[C:7](=[O:18])[C:8]=2[C:14]=1[CH3:15]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: Cc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 94.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (1.33 g, 94.2%) as an orange solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:42])=[N:13][C:14]2[N:15]([N:29]=[C:30]([C:32]3[CH:41]=[CH:40][C:39]4[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=4[CH:33]=3)[CH:31]=2)[C:16]=1[C:17]1[C:18]([CH3:28])=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:42])=[N:13][C:14]2[N:15]([N:29]=[C:30]([C:32]3[CH:41]=[CH:40][C:39]4[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=4[CH:33]=3)[CH:31]=2)[C:16]=1[C:17]1[C:18]([CH3:28])=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc(-c3ccc4c(c3)CCCC4)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Yield: 52.6 %

Procedure:
A solution of (2S)-methyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (22 mg, 0.038 mmol) and 1M NaOH (0.154 mL, 0.154 mmol) in MeOH (2 mL) was heated at 60° C. for 16 h. Then, the reaction mixture was cooled and purified by prep HPLC to afford (2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (12 mg, 0.020 mmol, 53.1% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.56 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 7.09 (d, J=7.9 Hz, 1H), 6.96 (d, J=10.7 Hz, 1H), 6.86 (s, 1H), 5.11 (s, 1H), 4.39-4.31 (m, 2H), 2.86-2.75 (m, 6H), 2.73 (s, 3H), 2.20-2.18 (m, 2H), 1.95 (s, 3H), 1.84-1.80 (m, 4H), 1.24 (s, 9H). LCMS (M+H)=558.4.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][C:13]1[N:18]2[N:19]=[C:20]([CH2:22][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[C:17]2[C:16]([CH3:42])=[N:15][CH:14]=1.[Cl-].[CH3:44][N:45]1[C:49]([CH:50]=O)=[N:48][C:47]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:46]1>O1CCCC1.C(Cl)Cl>[CH3:12][C:13]1[N:18]2[N:19]=[C:20]([CH2:22][CH2:50][C:49]3[N:45]([CH3:44])[N:46]=[C:47]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[N:48]=3)[N:21]=[C:17]2[C:16]([CH3:42])=[N:15][CH:14]=1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: Cn1nc(-c2ccccc2)nc1C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1ncc(C)n2nc(CCc3nc(-c4ccccc4)nn3C)nc12

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.16 mL, 1.07 mmol) was added to a stirred suspension of (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride (0.490 g, 1.07 mmol) and 2-Methyl-5-phenyl-2H-1,2,4-triazole-3-carbaldehyde (0.200 g, 1.07 mmol) in Tetrahydrofuran (6.9 mL) in dry THF (8 mL) and the mixture was stirred at room temperature under an atmosphere of Argon overnight. DCM (50 ml) was added and the organic phase was extracted with water (2×50 ml), dried (MgSO4) and the solvent was evaporated off.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]([O:11][CH3:12])=[N:8][C:7]([NH:13][CH:14]=[O:15])=[N:6][C:5]=2[N:4]([C@@H:16]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:17]2)[CH:3]=1.CC(C)C(O[C@@H]1[C@@H](COC(=O)C(C)C)O[C@@H](N2C3N=C(NC=O)N=C(OC)C=3C=C2)C1)=O.[I:66]N1C(=O)CCC1=O>C1CCCCC1>[CH3:22][CH:21]([CH3:23])[C:20]([O:19][C@@H:18]1[C@@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[O:26][C@@H:16]([N:4]2[C:5]3[N:6]=[C:7]([NH:13][CH:14]=[O:15])[N:8]=[C:9]([O:11][CH3:12])[C:10]=3[C:2]([I:66])=[CH:3]2)[CH2:17]1)=[O:24]
Reactant: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reactant: O=C1CCC(=O)N1I
Agent: COc1nc(NC=O)nc2c1ccn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Solvent: C1CCCCC1
Product: COc1nc(NC=O)nc2c1c(I)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reaction time: 23 h

Procedure:
Compound (46) is prepared as described for compound (45) by proceeding from compound (18) (500 mg, 1.11 mmol) and N-iodosuccinimide (264 mg, 1.16 mmol). The duration of the reaction is 23 h. Colorless crystals (590 mg, 92%) are obtained from cyclohexane. 1H-NMR ([D6] DMSO): δ=1.9 (d, J=7.0, CH3), 1.15 (d, J=7.0, CH3), 2.46, 2.60, 2.89 (3 m, CH and Hα,β-C(2′)), 4.06 (s, OCH3), 4.17 (m, H—C(5′)), 4.27 (m, H—C(4′)), 5.35 (m, H—C(3′)), 6.46 (m, H—C(1′)), 7.62 (s, H—C(6)), 9.55 (d, J=9.7, NH), 10.81 (d, J=9.9 HCO). Anal. calculated for C21H27JN4O7 (574.4): C 43.91, H 4.74, N 9.75; found: C 43.98, H 4.75, N 9.82.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.O1CCOCC1.[CH3:19][NH:20][CH2:21][CH2:22][OH:23]>O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CNCCO
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(CNCCO)n1
Temperature: 0 °C
Yield: 70 %

Procedure:
1.9 g (0.01 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 30 ml of dioxane, 5 ml of water and 1.6 ml (0.02 mol) of 2-methylaminoethanol are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 1.6 g of yellow powder are obtained, ie a yield of 70%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)=[CH:5][CH:4]=1.[C:35]1(=O)[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][NH:1][CH:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:4][CH:5]=4)[N:17]4[C:12]=3[C:13]([NH2:18])=[N:14][CH:15]=[N:16]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCCC1
Reactant: NCc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Product: Nc1ncnn2c(-c3ccc(CNC4CCCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 12 %

Procedure:
Using a procedure similar to that of Example 111 with 7-(4-Aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and cyclopentanone as starting materials, 29.3 mg (12%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.75 (s, 2 H) 3.00 (m, 1 H), 2.80-2.70 (m, 4 H), 2.50-2.40 (m, 4H); ES-MS m/z 514.16 [M+H]+, HPLC RT (min) 2.62.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.[F:14][C@@H:15]1[C@H:19]([OH:20])[C@@H:18]([CH2:21][OH:22])[O:17][C@H:16]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[OH-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:16]2[O:17][C@H:18]([CH2:21][OH:22])[C@@H:19]([OH:20])[C@H:15]2[F:14])=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: CCOc1nc(N)nc2nc[nH]c12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Temperature: 37 °C

Procedure:
2-Amino-6-ethoxypurine (0.8 g, 4.5 mmoles) which may be prepared according to R. W. Balsiger and J. A. Montgomery (J. Org. Chem. 25:1573, 1960) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.5 g, 2.1 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 50 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. The pH of the suspension was adjusted to 7.0 with KOH. Thymidine phosphorylase (4,000 I.U.) and purine nucleoside phosphorylase (14,000 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the reaction stirred at 37° C. On day 4, 2,000 I.U. of thymidine phosphorylase and 6,980 I.U. of purine nucleoside phosphorylase were added and the reaction was diluted to 250 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. On day 14, the solvent was removed under vacuum. The residue was suspended in water and methanol added to precipitate the protein. After the suspension was filtered, the filtrate was evaporated. The residue was dissolved in hot water and applied to a 1.5×15 cm column of anion exchange resin (Bio-Rad AG1X2 hydroxide form). After washing the column with water, the product was eluted with methanol/water (1/1). Product-containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilized to obtain title compound that analyzed as 0.7 hydrate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][CH2:12][CH2:13][Cl:14]>>[Cl:14][CH2:13][CH2:12][CH2:11][O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: ClCCCBr
Reactant: Cc1ccc(O)cc1C
Product: Cc1ccc(OCCCCl)cc1C

Procedure:
Prepared by Procedure U and Scheme AK using 3,4-dimethylphenol and 1-bromo-3-chloropropane.