Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)[CH:3]=1.[ClH:15]>C(O)C.[Pd]>[ClH:15].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)[CH:3]=1
Reactant: N#Cc1ccc(F)cc1-n1nccn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(F)cc1-n1nccn1
Reaction time: 4 h

Procedure:
Intermediate 77, 4-fluoro-2-1,2,3-triazol-2-yl-benzonitrile, (0.34 g, 1.8 mmol) was dissolved in ethanol (50 mL). 1N HCl (10 mL) was added along with a catalytic amount of 10%-Pd—C. The mixture was shaken under H2 at 55 psi for 4 h after which it was filtered through Celite and concentrated to give the title compound as the corresponding HCl salt. Yellow solid (0.402 g, 98% yield). 1H-NMR (500 MHz, CD3OD) δ ppm: 8.13 (2H, s), 7.87 (1H, dd, J=4.9, 2.6 Hz), 7.73 (1H, dd, J=4.9, 2.6 Hz), 7.34 (1H, td, J=8.2, 2.7 Hz), 4.35 (2H, s). LCMS [M+H]+ calcd for C9H10N4F: 193.08; found: 193.16.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.C([Mg]Cl)(C)C.[CH:24](=[O:27])[CH2:25][CH3:26]>C1COCC1>[OH:27][CH:24]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)[CH2:25][CH3:26]
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Reactant: CCC=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCC(O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
124-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (2.2 g, 6.21 mmol) in dry THF (150 mL) was cooled to −78° C. under Ar, and a 2M solution of iPrMgCl in THF (18.6 mL, 37.3 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and propionaldehyde (3.61 g, 62.1 mmol) was then added. The mixture was stirred at −78° C. for another 30 min and then allowed to warm to RT overnight. The reaction mixture was poured onto a saturated aq. solution of WWI and extracted with AcOEt. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, heptane to AcOEt/MeOH 9:1) to give the title compound (231 mg). UPLC-MS: MS 287.2 (M+H+); UPLC rt 0.59 min.
Reaction SMILES: [NH:1]1[C:5]2[NH:6][C:7]([C:9]([O:11]CC)=[O:10])=[CH:8][C:4]=2[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[NH:1]1[C:5]2[NH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH:3]=[N:2]1
Reactant: CCOC(=O)c1cc2cn[nH]c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cn[nH]c2[nH]1
Temperature: 80 °C
Yield: 20.4 %

Procedure:
Ethyl 1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylate (1.328 mmol, 0.238 g) was dissolved in ethanol (10 ml). Cesium carbonate (2.66 mmol, 0.866 g) dissolved in water (2 ml) was added and the resulting mixture was stirred at RT for a day after which more cesium carbonate (2.66 mmol, 0.866 g) dissolved in water (2 ml) was added. The temperature was raised to 80° C. for 7 h. Ethanol was evaporated and the residue was diluted with water. pH was adjusted to 4 with 2 M HCl and extracted three times with EtOAc and washed with water. The combined organics were dried, filtered and evaporated. 0.041 g of the title compound was obtained. LC-MS [M+1]: 152.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47]([F:50])([F:49])[F:48].COP(OC)OC>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]([F:50])([F:49])[F:48])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CC1(C)OB(c2cccc3[nH]c4c(c23)CCN(C(=O)c2ccccc2)CC4)OC1(C)C
Agent: [Pd]
Agent: COP(OC)OC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4C(F)(F)F)c3c2CC1
Yield: 95.1 %

Procedure:
3-Benzoyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (2.50 g, 6.00 mmol), triturated potassium phosphate (3.01 g, 14.2 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.562 g, 0.613 mmol) were combined in dioxane (63 mL) at rt under N2. 2-Bromobenzotrifluoride (0.98 mL, 1.62 g, 7.21 mmol) and trimethylphosphite (0.22 mL, 0.231 g, 1.86 mmol) were added to the reaction mixture by syringe. Ar was bubbled through the reaction mixture for 20 min. The reaction mixture was heated to reflux for 22 h. The reaction mixture was concentrated and the residue was taken up in toluene (150 mL) and H2O (200 mL). The layers were separated and the aqueous layer was extracted with toluene (1×100 mL, 1×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product (3.90 g) was chromatographed (SiO2 250 g, eluted with 2:1 toluene:EtOAc) to yield 3-benzoyl-10-[2-(trifluoromethyl)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (2.48 g) in 95% yield. IR (diffuse reflectance) 3294, 1617, 1575, 1461, 1439, 1423, 1346, 1334, 1316, 1276, 1266, 1259, 1178, 1170, 1126, 1113, 1105, 1058, 1034, 792, 775, 755, 719, 701, 626 cm−1; MS (ESI+) for C26H21F3N2O m/z 435.0 (M+H)+; Anal. Calcd for C26H21F3N2O: C, 71.88; H, 4.87; N, 6.45; found: C, 71.94; H, 4.93; N, 6.48.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[N:3]1[C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.Br[CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][CH:4]1[N:3]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:2]([CH3:1])[CH2:7][N:6]([CH2:23][CH2:24][OH:25])[CH2:5]1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC1CNCC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(CCO)CC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Temperature: 60 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
A mixture of 2-(2,6-dimethyl piperazine-1-yl)-6-trifluoromethyl benzothiazole (360 mg), (2-bromoethoxy)-t-butyldimethyl silane (257 uL), potassium carbonate (157 mg) and dimethylformamide (2 mL) was stirred at 60° C. for 20 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium carbonate. After evaporating the solvent, the residue was purified by column chromatograph on silica gel to give the title compound (265 mg). Yield: 65%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:12][C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:13]([NH:12][C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH3:14])=[CH:16][CH:17]=1
Reactant: Nc1cnccn1
Reactant: COC(=O)c1cc(Cl)nc(N[C@@H](C)c2ccc(F)cc2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
4.4 g of methyl (S)-2-chloro-6-[1-(4-fluorophenyl)ethylamino]isonicotinate, 1.3 g of 2-aminopyrazine, 2.67 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 5.0 g of tripotassium phosphate and 1.28 g of tris(dibenzylideneacetone)dipalladium were added in turn to 100 ml of degassed toluene, and the mixture was stirred at 100° C. for 24 hours under argon atmosphere. The reaction mixture was filtrated by celite, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 4.9 g of the objective compound as white powder.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:7][C:8]([C:10]1[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([CH3:20])[O:12][N:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.C(O)C>[C:3]([NH:7][C:8]([C:10]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:20])[O:12][N:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)c1c(C(=O)NC(C)(C)C)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1onc(C(=O)NC(C)(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
At from 5° to 10° C. and under a nitrogen blanket, 1.0 g (25.0 mmol) of sodium hydroxide in 50 ml of water was dripped into a solution of 5.4 g (21.3 mmol) of 4-ethoxycarbonyl-5-methyl-isoxazole-3-carboxylic acid-tert-butylamide in 100 ml of ethanol, and the mixture was stirred for 12 hours at room temperature. The solution was evaporated down, the residue was taken up in 150 ml of water, the pH was adjusted to 8-9, and the mixture was extracted twice, each time with 100 ml of diethylether. The aqueous phase was then acidified to a pH of 2 with 6N HCl, followed by extraction four times, each time with 200 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was stripped off under reduced pressure. Yield: 95%; yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([CH3:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[C:35]([CH3:36])=[C:34]2[C:29]([CH:30]=[C:31]([NH2:37])[CH:32]=[CH:33]2)=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:27]1[C:35]([CH3:36])=[C:34]2[C:29]([CH:30]=[C:31]([NH:37][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:10][CH:11]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:13][CH:12]5[CH2:23]4)[C:5]([CH3:24])=[CH:4][N:3]=3)[CH:32]=[CH:33]2)=[N:28]1
Reactant: Cc1cnc(Cl)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Reactant: Cc1c2ccc(N)cc2nn1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 150 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a suspension of tert-butyl 5-((2-chloro-5-methylpyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (421.5 mg, 1.19 mmol) and 2,3-dimethylindazol-6-amine hydrochloride (734.5 mg, 3.72 mmol) in n-BuOH (10 mL) was added DIPEA (795.2 mg, 6.09 mmol). The reaction mixture was stirred at 150° C. under microwave for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as brown oil (570.5 mg, 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].[CH3:13]O>S(=O)(=O)(O)O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CO
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1Cc2ccccc2N1

Procedure:
Indoline-2(S)-carboxylic acid (10 g, 64 mmol) was refluxed in a mixture of methanol (50 ml) and sulphuric acid (8 ml) for 5 h. The solvent was removed to give the product in the form of an oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17]>[N+](C1C=CC=CC=1)([O-])=O>[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5](=[O:15])[C:21]1[CH:22]=[CH:23][C:16]([OH:17])=[CH:18][C:19]=1[OH:20])([OH:10])=[O:9]
Reactant: Oc1cccc(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1ccc(O)cc1O
Reaction time: 8 h

Procedure:
2′-Carboxy-2,4-dihydroxybenzophenone was prepared according to literature procedures. Smith, G. A.; Metcalfe, J. C.; Clarke, S. D J. Chem. Soc. Perkin Trans 2. 1993, 1195. AlCl3 (28.00 g, 210 mmol) was added to a solution of phthalic anhydride (13.85 g, 93.5 mmol) and resorcinol (10.0 g, 90.8 mmol) in 225 ml nitrobenzene and purged with N2. After stirring overnight, the solution was poured into a vigorously stirred biphasic solution of 750 ml hexanes and 1.0 L 0.5 M aqueous HCl. The solution was allowed to stir for 2 h and the light tan precipitate that formed was filtered and washed with 200 ml aqueous 0.1 M HCl and 200 ml hexanes. The crude material was crystallized as light green plates from hot MeOH/H2O (9.90 g, 42%). 1H NMR (acetone-d6) δ 6.33 (1H, dd, J=9.0, 2.3 Hz), 6.39 (1H, d, J=2.3 Hz), 7.00 (1 H, d, J=9.0 Hz), 7.45 (1 H, d, J=7.5 Hz), 7.65-7.80 (2 H, m), 8.12 (1 H, d, J=6.7 Hz). FTIR (KBr, cm−1) 1693, 1627, 1594, 1568, 1521, 1490, 1444, 1356, 1284, 1267, 1228, 1187, 1154, 1123, 1083, 1022, 981, 967, 930, 852, 813, 784, 769, 736, 713, 697, 665, 624, 592, 535, 458.
Reaction SMILES: [C:1]1([S:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOCC1.[NH2:17][N:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23].[OH-].[Na+]>O>[O:23]=[C:19]1[NH:20][CH2:21][CH2:22][N:18]1[NH:17][C:8](=[O:9])[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Sc1ccccc1
Reactant: NN1CCNC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NN1CCNC1=O)Sc1ccccc1

Procedure:
3.2 ml. of (phenylthio)carbonyl chloride are dissolved in 30 ml. of dioxane and a solution of 2.63 g. of 1-amino-2-imidazolidinone in a mixture of 10 ml. of dioxane and 10 ml. of water is added. 2N sodium hydroxide solution is added dropwise at room temperature so that the pH is about 7.5-8.0. About 15 ml. of 2N sodium hydroxide are required. The dioxane is then distilled off. An oil separates which crystallizes after a short while to give 3.2 g. of (2-oxo-1-imidazolidinyl)carbamothioic acid, S-phenyl ester, m.p. 154°-159° (after recrystallization from ethyl acetate).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12].C(N(CC)C(C)C)(C)C.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](Cl)=[O:35]>C(Cl)Cl>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[C:3]([CH:8]=1)[CH2:2][NH:1][C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=1)=[O:35]
Reactant: NCc1cc(Br)ccc1NC(=O)c1ccccn1
Reactant: O=C(Cl)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cc(Br)ccc1NC(=O)c1ccccn1)c1ccccn1
Yield: 69.9 %

Procedure:
Compound 2-3 (0.050 g, 0.16 mmoles) was dissolved in 6 mL of methylene chloride. To the reaction vessel was added (0.06 mL, 0.32 mmoles) of N,N-diisopropylethylamine and (200 mg, 0.32 mmols, 1.49 mmol/gram) followed by the addition of (0.057 g, 0.32 mmol) picolinoyl chloride. The mixture was stirred until complete by TLC. The compound was then filtered and then the solvent was removed and then purified on a mass guided LC/MS to provide 46 mg (70%) of the title compound. 1H NMR (300 MHz, CDCl3): 8.89 ppm (s, 2H), 8.43 ppm (m, 2H), 8.22 ppm (m, 2H), 8.13 ppm (t, J=4 Hz, 1H), 8.0 ppm (s, 1H), 7.81 ppm (m, 2H), 7.41 ppm (m, 1H), 7.2 ppm (m, 2H), 4.22 ppm (d, J=4 Hz, 2H); HRMS calc'd for C19H15BrN4O2 (M+1) 411.0451; Found: 411.0444
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-])=O>CC(N(C)C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: Nc1ccc2c(c1)CC(=O)N2
Yield: 50.5 %

Procedure:
To a solution of 5-nitro-oxindole (25 g) in 120 mL of dimethylacetamide in a Parr bottle was added 10% Pd/C (0.5 g). The mixture was hydrogenated (40 psi H2) for 16 h. The catalyst was removed by filtration and the filtrate was diluted with ether (2 L) to provide 5-amino-oxindole (10.5 g; 50%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:7]=1.Br[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:16][N:15]1[C:11]([C:9]([NH:8][C:6]2[CH:7]=[C:2]([O:1][C:20]3[CH:25]=[N:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:3]=[CH:4][C:5]=2[CH3:18])=[O:10])=[CH:12][C:13]([CH3:17])=[N:14]1
Reactant: Cc1cc(C(=O)Nc2cc(O)ccc2C)n(C)n1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.8 %

Procedure:
A mixture of N-(5-hydroxy-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (4.67 g, 19.0 mmol), 5-bromo-2-nitropyridine (3.68 g, 18.1 mmol), cesium carbonate (9.29 g, 28.5 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=80/20→0/100) and then column chromatography (NH silica gel, hexane/ethyl acetate=80/20→0/100) to give the title compound (3.38 g, 44%) as a white solid.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:12]2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([NH2:41])[N:3]=1.[F:42][B-](F)(F)F.[H+]>>[CH2:14]([O:13][C@H:12]1[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:30]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:31][C@H:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([F:42])=[N:3][C:4]=2[NH2:41])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Agent: [H+]
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
The process of claim 1 wherein in addition the 2-amino group of (V) is replaced with a 2-fluoro group by reaction with fluoroboric acid in an organic solvent for the reaction to form 9-(2,3,5 tri-O-benzyl-beta-D-arabinofuranosyl)-2-fluoroadenine (VI) and wherein (VI) is treated in a reaction mixture with hydrogen and palladium chloride in an organic solvent and in a sealed vessel under pressure to produce 9-beta-D-arabinofuranosyl-2-fluoroadenine (VII) which is separated from the reaction mixture.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([NH:18][CH2:19][CH2:20][OH:21])[N:3]=1.CC(C)([O-])C.[K+].[CH2:28]([OH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([NH:18][CH2:19][CH2:20][OH:21])[N:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1c(Cl)nc(NCCO)c(C#N)c1-c1ccccc1
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#Cc1c(NCCO)nc(OCc2ccccc2)c(C#N)c1-c1ccccc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
58 mg (0.2 mmol) of 2-chloro-4-phenyl-6-(2-hydroxyethylamino)-3,5-pyridinedicarbonitrile (example 17, step 1) are, together with 27 mg (0.24 mmol) of potassium tert-butoxide, dissolved in 0.96 g (=1 ml, 8.9 mmol) of benzyl alcohol, and the mixture is stirred at 40° C. for about 16 h. The reaction mixture is purified by preparative HPLC on reversed-phase silica gel (gradient: water+0.1% formic acid/acetonitrile 90:105:95 in 35 minutes).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=1[O:29][C:30]1[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][N:31]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=2[O:29][C:30]2[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][N:31]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: Nc1ccnc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Product: Nc1ccnc(Oc2ccccc2-c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)n1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and 2-(2-bromophenoxy)pyrimidin-4-amine. MS (ESI): mass calcd. for C23H16FN5O, 397.13; m/z found, 398.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.47 (s, 1H), 8.11 (d, J=2.1, 1H), 7.96 (d, J=5.7, 1H), 7.54-7.30 (m, 9H), 6.07 (d, J=5.7, 1H), 4.96-4.85 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:15](Br)([N+:16]([O-:18])=[O:17])[CH2:14][CH:13]=[CH:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=[N+]([O-])C1(Br)CC=CCC1c1cc(F)c(F)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1-c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 500 mg (1.49 mmol) of 3,4,5-trifluoro-1-(6-bromo-6-nitrocyclohex-3-en-1-yl)-benzene from example 2.4 in 10 ml of toluene were added 200 mg (0.6 mmol) of tetrabutylammonium bromide and 15 ml of aqueous NaOH (4M) and the mixture was stirred for 24 h at room temperature. During the reaction, air was sparged through the mixture. Then the reaction mixture was stirred for another 12 h at 50° C. After cooling to room temperature, the phases were separated, the aqueous phase was extracted with ethylacetate (3×10 ml) and the organic phases were dried over Na2SO4. Column chromatography (SiO2, cyclohexane/ethylacetate 8:1) yielded 218 mg (0.86 mmol, 58% of theory) of the title compound as a reddish solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]=[C:7]2[CH2:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11][C:6]2=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>>[F:32][C:2]([F:1])([F:31])[C:3]1[N:8]=[C:7]2[CH2:9][NH:10][CH2:11][C:6]2=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc2c(n1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 2-Trifluoromethyl-6-trityl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine and trifluoroacetic acid. Light yellow solid. MS (m/e): 189.3 ([M+H+, 100%).