Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:30]([O:34][C:35]([NH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].[OH-].[Na+]>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([N:41]1[CH2:40][CH2:39][CH:38]([NH:37][C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:43][CH2:42]1)=[O:5]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 46 h
Yield: 112.7 %

Procedure:
N,N-Dimethylglycine (2.97 g), 1-hydroxybenzotriazole (3.89 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g) were added to a solution of 4-(tert-butoxycarbonylamino)piperidine (5.0 g) in N,N-dimethylformamide (70 ml), followed by stirring at room temperature under a nitrogen atmosphere for 46 hours. Ethyl acetate (400 ml), brine (200 ml) and a 1N aqueous solution of sodium hydroxide (50 ml) were added to the reaction mixture, followed by stirring at room temperature for 30 minutes, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layer was collected, washed with a 1N aqueous solution of sodium hydroxide and brine in this order, and dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure to give the title compound (8.03 g, quant.) as white crystals.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:37])[C:8]1=[O:38])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:38])[N:9]([CH3:37])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=2)=[CH:35][CH:34]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(C(F)(F)F)c3)cnc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(C(F)(F)F)c3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (45.3 mg, 0.083 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (6.93 mg, 0.165 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (8 mg, 18.6% yield) as a white solid. 1H NMR (CDCl3) δ: 8.82 (s, 1H), 8.35 (s, 1H), 8.26 (d, J=3.0 Hz, 1H), 7.53 (d, J=3.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.3 Hz, 2H), 4.26-4.20 (m, 4H), 3.71 (s, 3H), 3.58-3.54 (m, 2H), 2.97 (brd s, 1H), 1.96-1.90 (m, 2H). LCMS: MH+ 521 and TR=2.765 min.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.COC([C:13]1[NH:14][C:15]2[CH:16]=[C:17]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:18]=[C:19]3[C:25](=[O:26])[NH:24][N:23]=[CH:22][C:21]=1[C:20]=23)=O.CO.C(OCC)(=O)C>CN(C)C=O.C(Cl)(Cl)Cl>[C:31]([O:30][C:28](=[O:29])[NH:27][C:17]1[CH:18]=[C:19]2[C:25](=[O:26])[NH:24][N:23]=[CH:22][C:21]3=[C:13]([Cl:1])[NH:14][C:15]([CH:16]=1)=[C:20]23)([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc2c3c(c(Cl)[nH]c3c1)C=NNC2=O
Temperature: 50 °C
Yield: 89.8 %

Procedure:
N-Chlorosuccinimide (0.47 g, 3.52 mmol) was added to a solution of Intermediate 147(c) of Example 147 (1.00 g, 3.33 mmol) in anhydrous N,N-dimethylformamide (10 ml) and anhydrous chloroform (6.5 mL). The reaction was heated at 50° C. for 3 hours at which point the volatile components were removed in vacuo. The resulting residue was dissolved in methanol and loaded onto a silica gel plug. The plug was then loaded onto a silica gel column and eluted with 23:2:50 dichloromethane:methanol:ethyl acetate to afford the title compound (1 g, 2.99 mmol) as a yellow solid in 90% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O>>[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:2]1[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)[C:7]([C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Product: COc1ccccc1-c1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 2-methoxyphenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C.O>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(O)CCl
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(O)COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 36.7 %

Procedure:
A solution of 8.15 g (0.075 mol) of 1-chloro-2-methyl-2-propanol in 20 ml of ethanol is run over the course of 25 minutes into a solution, kept at about 60° C., of 15 g (0.068 mol) of p-(p-chlorophenoxy)phenol and of 3 g (0.075 mol) of sodium hydroxide pellets in 20 ml of water and 20 ml of ethanol. The mixture is heated to the reflux temperature for 2 hours and the ethanol is driven off under reduced pressure. The residue is extracted with diethyl ether and after drying and evaporation of the solvent gives 7.3 g of a yellow oil. This oil is purified by crystallisation from a mixture of cyclohexane and petroleum ether (1:2 by volume) followed by washing with 2 N NaOH. 4 g of a white powder which is insoluble in water are obtained.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:31]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1)([CH3:33])[CH3:32].Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([CH:31]([CH3:33])[CH3:32])=[CH:35][CH:36]=3)[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)cc1
Reaction time: 8 h
Yield: 36.3 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (1.0 g, 7.24 mmoles) and 4-isopropylbenzyl chloride (250 mg, 1.5 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (161 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (s, 1 H), 10.14 (s, 1 H), 7.16-7.24 (m, 4 H), 4.95 (s, 2 H), 4.64 (t, J=11.37 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.79-2.90 (m, J=6.86, 6.86, 6.86, 6.86, 6.86, 6.86 Hz, 1 H), 2.20-2.32 (m, 2 H), 1.78 (d, J=12.88 Hz, 2 H), 1.62 (d, J=11.12 Hz, 3 H), 1.22-1.34 (m, 2 H), 1.09-1.20 (m, 7 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]([CH3:31])[C:13]([C:15]1[S:30][C:18]2[C:19]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:14].C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]([CH3:31])[C:13]([C:15]1[S:30][C:18]2[C:19]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:33])[CH:25]=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:14]
Reactant: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2cc(C#N)ccc2OCC3)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2cc(C(N)=O)ccc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(2-chloro-4-(methylcarbamoyl)phenyl)-9-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 298 (100 mg) and potassium carbonate (37 mg) in DMSO (3 mL) at 0° C. was added hydrogen peroxide (30 μL of a 33% solution in water). The reaction was stirred at room temperature for 16 h. Water was then added and the resulting solid collected by filtration and air-dried to give 306. NMR: (DMSO): 2.81 (3 H, d, J 4.5, Me), 2.91-2.93 (2 H, m), 3.68 (3 H, s, Me), 4.19-4.22 (2 H, m), 6.41 (1 H, s, NH), 7.03 (1 H, d, J 8.4, Ar), 7.35 (1 H, s), 7.71-7.77 (2 H, m, Ar), 7.92 (1 H, dd, J 8.3 and 2.0, Ar), 8.03-8.05 (3 H, m) and 8.65-8.67 (1 H, m). MS: (ESI+) MH+ 469.35
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH:41]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:39]=[N:38]2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([N:37]2[CH:41]=[C:40]([C:2]3[C:6]4[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]5[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=5[Cl:22])[CH3:13])[C:5]=4[O:4][CH:3]=3)[CH:39]=[N:38]2)[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-furo[3,2-c]pyridin-6-ylamine (601 mg, 1.43 mmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (810 mg, 2.1 mmol) and potassium carbonate (590 mg, 4.3 mmol) in 1,4-dioxane (10 mL) and H2O (3 mL) was degassed and refilled with argon (3×) prior to the addition of PdCl2(dppf) (105 mg, 0.143 mmol). The reaction mixture was degassed and refilled with argon (2×) and heated at 100° C. for 2 h (conventional heating). The mixture was diluted with EtOAc (60 mL), then washed with brine (20 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex:EtOAc=50:50→20:80→100% EtOAc) to give the title compound as a light-yellow solid. LC-MS (ES+): 590.07/592.09 [MH+]. 1H NMR (CDCl3, 400 MHz): δ 1.49 (s, 9H), 1.90 (d, J=6.8 Hz, 3H), 1.91-2.02 (m, 2H), 2.17-2.20 (m, 2H), 2.93 (m, 2H), 4.27-4.36 (m, 3H), 5.24 (br s, 2H), 6.62 (q, J=6.8 Hz, 1H), 7.07 (dd, J=8.8, 7.8 Hz, 1H), 7.30 (dd, J=8.8, 4.8 Hz, 1H), 7.55 (s, 1H), 7.68 (s, 1H), 7.75 (s, 1H), 8.11 (s, 1H).
Reaction SMILES: [C:1]1([NH2:12])[C:6]([F:7])=[C:5]([F:8])[C:4]([F:9])=[C:3]([NH2:10])[C:2]=1[F:11].[ClH:13].Cl.[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][CH:31]([CH2:33][NH:34]C(C3C=CC=CC=3)C)[O:30][C:29]2=[O:43])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>[OH-].[OH-].[Pd+2].CO>[C:1]1([NH2:12])[C:6]([F:7])=[C:5]([F:8])[C:4]([F:9])=[C:3]([NH2:10])[C:2]=1[F:11].[ClH:13].[ClH:13].[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][CH:31]([CH2:33][NH2:34])[O:30][C:29]2=[O:43])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1)c1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1

Procedure:
To a reaction flask were added 3.0 g of dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl)-5-[(1-phenylethyl)aminomethyl]-1,3-oxazolidin-2-one (4a), 100 ml of methanol and 1.0 g of 10% Pd(OH)2/C. Gas inside the reaction flask was evacuated and argon was then introduced to the reaction flask. The reaction mixture was allowed to react for 48 hours at room temperature with stirring. After the reaction was completed, the reaction mixture was filtered, and subsequently put under reduced pressure for solvent removal to give a dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl-5-aminomethyl-1,3-oxazolidin-2-one (5a) as a white solid and at a yield of 95%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:16]CCCC)=[C:8]([C:13](=O)[CH3:14])[C:9]([OH:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].O.[NH2:22]N>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:16][N:22]=[C:13]([CH3:14])[C:8]=2[C:9]([OH:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: NN
Reactant: CCCCNc1c(C(=O)OCC)cnc(O)c1C(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(O)c2c(C)n[nH]c12

Procedure:
8.4 g. of 3-acetyl-4-butylamino-2-hydroxypyridine-5-carboxylic acid ethyl ester (0.03 mol.) are dissolved in 20 ml. of acetic acid, 3 ml. of hydrazine-hydrate are added and the mixture is refluxed for 5 hours. After this time, the solvent is removed in vacuo and the crystalline precipitate of 4-hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester is recrystallized from acetic acid, yield 5.1 g. (77%), m.p. 310°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33]O)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33][O:1][C:2]2[CH:3]=[C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCCN(C(=O)OC(C)(C)C)C2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in step c of Example 3, N-(tert-butoxycarbonyl)-3-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step a of Example 2, and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (15 mL) at 0° C. was treated with diethyl azodicarboxylate (349 mg, 2.0 mmol). The reaction mixture stirred at 0° C. for 2 h and at room temperature for 3 h. Water (50 mL) was added and the reaction mixture was extracted into ethyl acetate (3×50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo The residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a colorless syrup (875 mg, 88%). 1H-NMR (300 MHz, CDCl3) δ 1.28 (m, 1H), 1.45 (s, 9H), 1.64-1.96 (m, 4H), 2.23 (s, 3H), 2.87 (M, 2H), 3.69 (m, 2H), 3.90 (d, 2H), 6.46 (s, 1H), 6.52 (s, 1H), 6.58 (s, 1H), 7.40 (t, 1H), 7.62 (m, 2H), 7.96 (d, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21]>C1COCC1.CCCCCC>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:13]2=[O:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=C1CCCCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1CCCCC1Cc1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of diisopropylamine (342 mL, 2.45 mmol, 1.2 equiv) in 5 mL of anhydrous THF at 0° C. was added n-butyllithium (1.63 mL of a 1.6M solution in hexane), and the mixture was stirred at this temperature for 15 minutes before cooling to -78° C. Cyclohexanone (221 mL, 2.04 mmol, 1.0 equiv) in 2 mL of anhydrous THF was then added dropwise, stirred at -78° C. for 1 h followed by p-nitrobenzyl bromide (880 mg, 4.08 mmol, 2.00 equiv) in 2 mL of THF, added dropwise to the resulting enolate. The reaction mixture was stirred at room temperature for 17 h, and then quenched with aqueous saturated NH4Cl, and extracted with ether. The organic phase was dried over Na2SO4 and concentrated under diminished pressure to a solid residue that was purified by flash chromatography (silica gel, hexanes/ethyl acetate, 85:15), which afforded 300 mg (64%) of the desired ketone as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.41 (m, 1H), 1.66 (m, 2H), 1.88 (m, 1H), 2.08 (m, 2H), 2.33 (m, 1H), 2.45 (m, 1H), 2.57 (m, 1H, 2-H), 2.59 and 3.29 (d of ABq, 2H, benzylic-CH2), 7.34 (d, 2H, Ar--H), 8.12 ppm (d, 2H, Ar--H). [This compound is also referred to as Compound "F" or 120138]
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5]>C(O)C.Cl.O>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)c1C#N
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)c(Cl)c1C#N
Yield: 31.8 %

Procedure:
A solution of 2-chloro-6-methyl-3-nitrobenzonitrile (6.3 g) in ethanol (23 ml) was added to a solution of stannous chloride dihydrate (21.7 g) in concentrated hydrochloric acid (19 ml). The mixture was then heated at reflux for 15 minutes, cooled and diluted with water (200 ml). The fine white powder which precipitated was separated, dried and crystallized from ethanol (10 ml) to give 2-chloro-3-cyano-4-methylaniline (1.7 g), m.p. 117°-119° C., in the form of colourless crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>>[F:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1c(F)cccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1c(F)cccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 11.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (125 mg, 0.26 mmol) obtained in Example 55, step 2 and cyclopropanesulfonamide (160 mg, 1.32 mmol), the title compound (17 mg, 11%) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH2:7]([O:14][C:15](=[O:28])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22]OS(C)(=O)=O)=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:7]([O:14][C:15](=[O:28])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:20][CH:21]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)OCc1ccc(C(=O)OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCNCc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
N,N-Dimethylethylenediamine (0.90 mL, 8.2 mmol) was added to a solution of 4-methanesulfonyloxymethylbenzoic acid benzyl ester (Reference Compound No. 6-1, 2.3 g, 7.2 mmol) and triethylamine (3.0 mL, 22 mmol) in DMF (10 mL), and then the reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution (0.15 L) was added to the reaction solution, and the whole was extracted with chloroform (0.10 L) three times. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 1.2 g of mixture including the title reference compound as yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22](N)=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2].[I:30]CI.CCCCCON=O>C(#N)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:30])=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2]
Reactant: ICI
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCCCON=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
To a solution of (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-(2-amino-6-chloropurin-9-yl)oxolan-3-yl acetate (3.8 g, 8.88 mmoles) in acetonitrile (40 ml) was added diiodomethane (3.4 ml) and n-amyl nitrite (8.2 ml). The resulting mixture was refluxed overnight, then the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with a mixture of 40% ethanol/60% hexane, to provide (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-(6-chloro-2-iodopurin-9-yl)oxolan-3-yl acetate (2.7 g) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:20]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: ClCc1cc(-c2ccccc2)no1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2ccccc2)no1

Procedure:
Synthesized in a manner similar to Example 23 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-(chloromethyl)-3-phenylisoxazole: 1H NMR (400 MHz, acetone-d6) δ 8.06 (d, J=8.6 Hz, 1H), 7.84-7.80 (m, 2H), 7.69 (d, J=8.4 Hz, 1H), 7.48-7.44 (m, 3H), 6.88 (s, 1H), 6.69 (s, 1H), 5.86 (s, 2H), 2.69 (s, 3H).