Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].FC(F)(F)C(O)=O.N(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+]>>[Cl:8][C:3]1[C:2]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: OCC(F)(F)F
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1cccnc1Cl
Temperature: 55 °C
Yield: 62.6 %

Procedure:
A reactor vessel is charged with 3-amino-2-chloropyridine (2.7 g, 21 mmol), 2,2,2-trifluoroethanol (15 g, 150 mmol), and trifluoroacetic acid (3.63 g, 31.8 mmol). The solution is cooled to the range 0° C. to 5° C. and then the reagent t-butyl nitrite (2.51 g of a 96% solution, 23.4 mmol) is added drop-wise to the vessel maintaining the temperature in the range 0° C. to 5° C. After stirring a few minutes the solution is transferred drop-wise to a reactor vessel containing 2,2,2-trifluoroethanol (20 g, 200 mmol) maintained at 55° C. The temperature rose to 70° C. during the drop-wise addition of the diazonium salt reaction mass. After cooling the solution, it neutralized with aqueous saturated sodium bicarbonate solution and then extracted with MTBE. The solvent is removed by evaporation to obtain 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (3.36 g) with an actual yield of 62.6%.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])=[C:10]([OH:25])[C:9]3[CH2:26][S:27][CH2:28][C:8]2=3)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:25])[C:9]3[CH2:26][S:27][CH2:28][C:8]2=3)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)CSC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)CSC2
Temperature: 40 °C

Procedure:
To tert-butyl N-{[1-(4-bromobenzyl)-4-hydroxy-2-oxo-1,2,5,7-tetrahydrothieno[3,4-b]pyridin-3-yl]carbonyl}glycinate (prepared in similar fashion to Reference Example 3 and the preceding Reference Examples, 1.007 g, 2.033 mmol) was added CH2Cl2 (10.0 mL) and TFA (2.0 mL) at rt. After 1 hr the reaction was heated to 40° C. for an additional 4 h. The reaction was concentrated and then diluted with Et2O and MeOH to crystallize the sample. The liquid was decanted away and the solid was washed twice with hexane to afford the title compound. HPLC/MS: 438.9.0 (M+1); Rt=3.38 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:34]
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A177) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]([F:24])([F:23])[F:22])(=O)=O.[CH2:25]([O:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32]C)=[O:30])[CH3:26].C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1>[F:22][C:21]([F:24])([F:23])[C:9]1[N:8]([CH2:7][CH2:6][O:5][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][CH:28]([O:27][CH2:25][CH3:26])[C:29]([O:31][CH3:32])=[O:30])=[CH:40][CH:39]=2)[C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[N:10]=1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CS(=O)(=O)OCCn1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(Cc1ccc(OCCn2c(C(F)(F)F)nc3cc(C(F)(F)F)ccc32)cc1)C(=O)OC

Procedure:
2-[2,5-bis(trifluoromethyl)-1H-benzimidazol-1-yl]ethyl methanesulfonate (1.88 g, 5 mmol) and ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (1.19 g, 5 mmol) were taken in toluene (20 ml) and K2CO3 (1.38 g, 10 mmol) was added. The reaction mixture was heated under reflux for 30 hrs. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The organic layer was dried and evaporated to the product which was purified by column chromatography on silica gel using ethyl acetate and hexanes as the solvent system (2.01 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12]([OH:15])(=O)=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.S(Cl)([Cl:18])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:12]([Cl:18])(=[O:15])=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)c(S(=O)(=O)O)cc2o1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)c(S(=O)(=O)Cl)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a stirred mixture of 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonic acid (˜10 g, 40 mmol) and CH2Cl2 was added thionyl chloride (5.8 cm3, 80 mmol) at room temperature, causing gas to be evolved. This was stirred at room temperature for two hours but the solid didn't dissolve and FIA only showed starting material. Therefore a few drops of DMF were added and the reaction heated to 50° C. overnight but no reaction occurred. The starting material was filtered off and then treated with neat thionyl chloride (15 cm3) and heated to 70° C. overnight, FIA now detected starting material and product, so the reaction was treated with DMF (2×1 cm3) to aid solvation, FIA showed completion of the reaction. The reaction was diluted with CH2Cl2 (100 cm3) then poured onto ice. The solid formed was filtered off and dried in vacuo yielding 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl chloride (4.6 g, 43%) as a fine white solid; δH (300 MHz; D6 DMSO) 7.09 (1H, s, Ar—H), 7.69 (1H, s, Ar—H) and 11.81 (1H, s, N—H); m/z (FIANEG) 266.0 [(M−H)−, 100%] and 268.0 [(M−H)−, 67%].
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:9]([NH2:10])=[C:8]([CH2:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+]>O.Cl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:9](=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[CH:12]=1)[NH:10][N:1]=[C:20]2[S:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: O=N[O-]
Reactant: CN1CCN(c2cc(Cl)cc(CS(=O)(=O)c3ccc(F)cc3)c2N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2cc(Cl)cc3c(S(=O)(=O)c4ccc(F)cc4)n[nH]c23)CC1
Temperature: 25 °C

Procedure:
A solution of NaNO2 (22.0 mg) in water at 0° C. is treated dropwise with a solution of 4-chloro-2-{[(4-fluorophenyl)sulfonyl]methyl}-6-(4-methylpiperazin-1-yl)aniline (102.2 mg, 0.25 mmol) in 1M HCl, allowed to warm to room temperature over a 2 h period, treated with saturated Na2CO3 to pH>10 and filtered. The filtercake is washed with water and dried in vacuo to give the title compound, identified by mass spectral and NMR analyses.
Reaction SMILES: [N:1]([CH:4]([C:17]1[CH:18]=[C:19]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[O:20][CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:1][CH:4]([C:17]1[CH:18]=[C:19]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[O:20][CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](CC)(CC)CC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCC(N)c1coc([Si](CC)(CC)CC)c1

Procedure:
Reacting 4-(1-hydroxytridecyl)-2-triethylsilylfuran with diphenylphosphonyl azide and diethyl azidocarboxylate gives 4-(1-azidotridecyl)-2-triethylsilylfuran. Reducing this azide with lithium aluminum hydride gives 4-(1-aminotridecyl)-2-triethylsilylfuran. Acetylation of this intermediate with acetic anhydride gives 4-(1-acetamido)tridecyl-2-triethylsilylfuran. Oxidizing this amide with oxygen using Rose Bengal as an initiator gives 4-(1-acetamido)-5-hydroxy-2(5H)-furanone. Reduction of this furanone with sodium borohydride gives 4-(1-acetamido)-2(5H)-furanone.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[NH:7][NH2:8].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:11]([O:10][C:6]([NH:7][NH:8][CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)NN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NNC1CCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24.9 %

Procedure:
Cyclobutanone (8.19 g, 116.85 mmol) was dissolved in ethanol (60 mL). tert-Butyl carbazate (15.64 g, 118.34 mmol) was added. The reaction was stirred at 25° C. for 2.5 h before it was concentrated in vacuo. The residue was re-dissolved in ethanol (60 mL). Acetic acid (14.09 mL, 246.14 mmol) and sodium cyanoborohydride (15.46 g, 246.02 mmol) were added. The reaction was stirred at 25° C. for 48 h. The reaction was quenched via slow addition of saturated aqueous sodium bicarbonate solution (until pH 8 was reached). The resulting mixture was extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-30% ethyl acetate in hexanes) afforded the desired product, N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (5.42 g, 29.10 mmol, 25%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.62-1.70 (1H, m), 1.73-1.82 (1H, m), 1.84-1.94 (2H, m), 2.07-2.15 (2H, m), 3.56-3.63 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[N:12]=[C:11](SC)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+:15].[Cl-]>CO>[C:1]([O:5][C:6]([C@H:8]1[N:12]=[C:11]([NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CSC1=N[C@H](C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CCC(N)=N1

Procedure:
To a solution of (S)-2-methylsulfanyl-3,4-dihydro-5H-pyrrole-5-carboxylic acid t-butyl ester (0.42 g, 1.95 mmol) in 4.0 mL anhydrous MeOH was added anh NH4Cl (0.11 g, 2.05 mmol). The reaction mixture was heated to reflux for 2 h, concentrated in vacuo, and the residue was taken up in CH2C2. The white solids were filtered, and the filtrate was concentrated to provide (S)-2-amino-3,4-dihydro-5H-pyrrole-5carboxylic acid t-butyl ester.HCl (0.41 g, 94%) as a light yellow solid 1H NMR (CDCl3) δ 1.49 (s, 9H), 2.24 (m, 1H), 2.52 (m, 1H), 3.06-3.08 (m, 2H), 4.44 (m, 1H), 9.81-9.8 (m, 2H). MS calcd for C9H16N2O2 +H 185, found 185.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.C(Cl)[Cl:24]>CN(C1C=CN=CC=1)C>[Cl:24][CH2:14][C:12]1[O:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: ClCCl
Reactant: CC1(c2ccc(CO)o2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Product: CC1(c2ccc(CCl)o2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-methanol (3.20 g, 17.37 mmol) in dry CH2Cl2 (32.0 mL) was treated at 0° C. with Et3N (3.14 mL, 22.59 mmol) followed by DMAP (212 mg, 1.74 mmol) and Ms-C1 (1.62 mL, 20.85 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (30 mL), extracted with CH2Cl2 (30 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 4.49 g of crude 2-(5-chloromethyl-furan-2-yl)-2-methyl-[1,3]dioxolane as an brown oil. The crude material in acetone (43 mL) was treated, under inert atmosphere (N2) with 4-nitro-2H-[1,2,3]triazole (1.97 g, 17.27 mmol), K2CO3 (7.16 g, 51.82 mmol) followed by TBA bromide (1.11 g, 3.45 mmol). The reaction mixture was stirred for 2 days at rt. Water (30 mL), followed by EA (40 mL) was added. The aq. layer was extracted with EA (40 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as an orange oil: TLC:rf (60:40 hept-EA)=0.28. LC-MS-conditions 02: tR=0.95 min; [M+H]+=281.01.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=O)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.[CH3:52][S:53]([CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)(=[O:55])=[O:54]>CC(N(C)C)=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:59]3[CH2:60][CH2:61][CH:56]([S:53]([CH3:52])(=[O:55])=[O:54])[CH2:57][CH2:58]3)=[O:15])[N:10]=[C:9]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Reactant: CS(=O)(=O)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CS(=O)(=O)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (150 mg, 0.48 mmol) in DMA (3 mL) at room temperature was added HOBt (72 mg, 0.53 mmol), EDCI (102 mg, 0.53 mmol), NMM (0.13 mL, 1.20 mmol) and 4-(methylsulfonyl)piperidine (117 mg, 0.72 mmol) and the mixture sonicated to a fine suspension and stirred for 18 hours at room temperature. The volatiles were removed under high vacuum and the residue partitioned between EtOAc (70 mL) and water (25 mL). The aqueous layer was removed and the organics washed with NaHCO3 (30 mL), brine (30 mL), dried over MgSO4, filtered and stripped to yield the title compound as an off-white solid, 144 mg, 66%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.46-8.56 (2 H, m), 7.60-7.71 (2 H, m), 7.25-7.37 (2 H, m), 7.07-7.19 (2 H, m), 6.53 (1 H, s), 5.10-5.41 (2 H, m), 4.40 (1 H, d, J=13.14 Hz), 3.97-4.15 (1 H, m), 3.95 (2 H, s), 3.34-3.49 (1 H, m), 3.12 (1 H, t, J=12.00 Hz), 2.96 (3 H, s), 2.64 (1 H, t, J=11.62 Hz), 2.06 (2 H, d, J=12.88 Hz), 1.59-1.79 (1 H, m), 1.36-1.54 (1 H, m); m/z (APCI+) for C23H25N4O3F 457.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]3)=[O:16])[NH:12][C:9]2=[N:10][CH:11]=1.Cl.[CH3:26][C@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:23][C:20]1([F:24])[CH2:21][CH2:22][N:17]([C:15]([C:13]2[NH:12][C:9]3=[N:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]4[CH2:29][CH2:30][CH2:31][C@@H:27]4[CH3:26])[CH:7]=[C:8]3[CH:14]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: C[C@H]1CCCN1
Reactant: O=C(c1cc2cc(OCCCCl)cnc2[nH]1)N1CCC(F)(F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCCN1CCCOc1cnc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Yield: 57 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from [5-(3-chloro-propoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, (S)-2-methyl-pyrrolidine hydrochloride (commercially available) and potassium carbonate in acetonitrile to give the desired product as a colorless solid (57%).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:27]=3)[CH:17]=2)=[CH:11][C:10]=1[CH3:40])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:27]=3)[CH:17]=2)=[CH:11][C:10]=1[CH3:40]
Reactant: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc(C)c1O

Procedure:
0.35 g of 5-(4-benzyloxy-3,5-dimethylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine is hydrogenated in a hydrogen atmosphere at normal pressure and about 50° C. for 2 h in 15 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and chromatography on silica gel using methylene chloride/methanol 10:1, after crystallization from methylene chloride, 5-(4-hydroxy-3,5-dimethylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine having an m.p. of 150°-152° C. is obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:18]([CH3:19])=[N:17][C:10]2[N:11]=[C:12]([NH:15][CH3:16])[N:13]=[CH:14][C:9]=2[CH:8]=1)(=O)=O.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:24]=1[NH2:25].C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[NH2:25][C:24]1[C:23]([F:22])=[CH:29][C:28]([CH3:30])=[C:27]([C:7]2[C:18]([CH3:19])=[N:17][C:10]3[N:11]=[C:12]([NH:15][CH3:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)[CH:26]=1
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CNc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Temperature: 60 °C
Yield: 88.6 %

Procedure:
Combine 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (1.15 g, 3.57 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.896 g, 3.57 mmol), and NaHCO3 (0.899 g, 10.71 mmol) in dioxane (24 mL) and H2O (6 mL), sparge with argon, treat with Pd(PPh3)4 (0.206 g, 0.178 mmol) and heat to 60° C. overnight. Add additional 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (120 mg, 0.37 mmol) and Pd(PPh3)4 (80 mg, 0.07 mmol), sparge the mixture with argon, and heat at 60° C. overnight. Cool the mixture to RT, treat with brine and extract with EtOAc (3×). Wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (50-100% EtOAc/Hexanes) to afford the title compound (940 mg, 89% yield). MS (m/z): 298.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=2)[CH2:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>CC(O)=O.CCOC(C)=O>[CH:1]1([C:4]2[N:9]=[C:8]([OH:10])[C:7]([N+:12]([O-:14])=[O:13])=[C:6]([OH:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)nc(C2CC2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)cc(C2CC2)nc1O
Temperature: 30 °C
Reaction time: 8 h
Yield: 514 %

Procedure:
6-Cyclopropyl-2,4-dihydroxy-pyridine (1 g, 6.6 mmol) was suspended in AcOH:EtOAc (4:1, 10 mL) at room temperature. The mixture was warmed to 30° C. and a small portion of fuming nitric acid (0.05 ml, 1.2 mmol) was added dropwise, keeping the temperature between 30 and 35° C. Upon addition the mixture became a clear solution. The remainder of the fuming nitric acid (0.25 ml, 6.3 mmol) was added dropwise. The clear solution was allowed to cool to room temperature upon which a precipitate started to form. The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with cold water and Et2O and dried in vacuo at room temperature over the weekend to give the title compound (1.21 g) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O.FC1C=C2C(=CC=1)C=[N:18][CH:17]=[CH:16]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8]([CH:16]=[CH:17][N:18]=[CH:6]2)=[CH:9][C:10]=1[F:11]
Reactant: Fc1ccc2cnccc2c1
Reactant: COc1cc(C=O)ccc1F
Product: COc1cc2cnccc2cc1F

Procedure:
Starting from 3-methoxy-4-fluoro-benzaldehyde, the title compound was prepared by the same reaction sequence as 6-fluoro-isoquinoline (5). Rt=0.70 min (Method #4). Detected mass: 178.1 (M+H+).
Reaction SMILES: C(O[C:4](=[NH:15])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[CH3:16][C:17]1[S:21][C:20]([C:22]([NH:24][NH2:25])=[O:23])=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[NH2:15][C:4](=[N:25][NH:24][C:22]([C:20]1[S:21][C:17]([CH3:16])=[CH:18][CH:19]=1)=[O:23])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: Cc1ccc(C(=O)NN)s1
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)NN=C(N)CS(=O)(=O)c2ccccc2)s1
Yield: 91.2 %

Procedure:
1.75 g (0.0077 Mol) of 2-(phenylsulfonyl)-ethanimidic acid ethyl ester was stirred together with 1.2 g (0.0077 mol) 5-methyl-thiophen-2-carboxylic acid hydrazide in 14 ml chloroform for 24 hours at 50° C. The resulting precipitate was filtered off and dried. 2.37 g of 5-methyl-thiophen-2-carboxylic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as off-white crystals. Mp.: 222° C. (dec.).
Reaction SMILES: [C@@H:1]1([N:10]2C=CC(N)=NC2=O)[O:9][C@H:6]([CH2:7]O)[C@@H:4](O)[C@H:2]1O.[C:18](OC(=O)C1C=CC=CC=1)(=O)[C:19]1C=CC=CC=1>CN(C=O)C>[C:1]([NH2:10])(=[O:9])[C:2]1[CH:4]=[CH:6][CH:7]=[CH:19][CH:18]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 282.4 %

Procedure:
To a suspension of cytidine (100 g, 0.411 mol) in DMF (2.06 L) is added benzoic anhydride (102.4 g, 0.452 mol). The mixture was stirred at room temperature for 20 h. The DMF was removed in vacuo and the residue was triturated with diethyl ether. The resulting solid was collected by suction filtration and washed with diethyl ether (2×200 mL). Further drying in vacuo at room temperature gave the N4 benzamide (140.6 g, 98.3%). A portion of this material (139.3 g, 0.401 mol) was dissolved in anhydrous pyridine (1.2 L) and was treated with 1,3-dichloro-1,1,3,3-tetraisopropyl-disiloxane (141.4 mL, 0.441 mol) at room temp. The solution was stirred at room temperature overnight. The mixture was concentrated to near dryness in vacuo and coevaporated with toluene (3×200 mL). The residue was treated with EtOAc (1.8 L) and washed with HCl (2×200 mL, 0.05 N), NaHCO3 (5%, 2×400 mL). The organic layer was washed, dried (Na2SO4), filtered, and evaporated to dryness. Compound 16-1 (Compound 4-1 from U.S. Pat. No. 7,429,572) (256.5 g, >100%) was isolated as a white foam and used without further purification.