Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[OH-].[Na+].Cl>C1COCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(-c2ccc(N)c(NC(=O)c3ccc(OC)cc3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(C(=O)O)cc3)ccc2N)cc1
Yield: 80.3 %

Procedure:
A solution of 104 (44 mg, 0.117) and NaOH 1M (0.24 ml, 0.24 mmol) in THF (1 ml) and water (1 ml) was stirred 48 h at 40° C. HCl 1M was added and the precipitate was filtered out. The solid was further purified by flash chromatography (eluent 3-5% MeOH in DCM), to give the compound 105 (34 mg, 80% yield). 1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.58 (d, J=2.0 Hz, 1H), 7.40 (dd, J=8.2, 2.0 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.4 Hz, 1H), 5.23 (s, 2H), 3.84 (s, 3H). MS: (calc.) 362.1; (obt.) 363.1 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][NH:9][CH2:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Brc1cnc2c(c1)CNC2
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of 3-bromo-6-trityl-5,7-dihydropyrrolo[3,4-b]pyridine (1.57 g, 3.66 mmol) in chloroform (15 mL) and methanol (15 mL) was added trifluoroacetic acid (30 mL) over 1 min. On complete addition, the solution was stirred for 5 min then the cold bath removed and stirring continued for 30 min. This solution was concentrated under reduced pressure and the residue taken up in HCl (30 mL, 1M aq.). This mixture was extracted with ether (2×20 mL) then the aqueous phase basified with sodium hydroxide (5M aq.). This mixture was extracted with dichloromethane (3×20 mL). The combined dichloromethane extract was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@H:21]([O:23][CH3:24])[CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][C@H:21]([O:23][CH3:24])[CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@H](OC)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1C[C@H](Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)[C@@H](c2ccnn2C)C1
Yield: 81.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (65.0 mg, 0.106 mmol) prepared in Example 121d, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (40.0 mg, 81%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH:11]([C:19]1[NH:20][C:21](=[O:37])[C:22]([OH:36])=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:26])[N:24]=1)[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][OH:16])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(C#N)(C)=O.C(Cl)Cl.O>[CH3:38][S:39]([O:37][C:21]1[C:22]([O:36][S:39]([CH3:38])(=[O:41])=[O:40])=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:26])[N:24]=[C:19]([CH:11]([N:3]([C:4]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:10])[CH2:1][CH3:2])[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][O:16][S:39]([CH3:38])(=[O:41])=[O:40])[N:20]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)[nH]1
Agent: CC(=O)C#N
Solvent: O
Solvent: ClCCl
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](COS(C)(=O)=O)OC)c1nc(OS(C)(=O)=O)c(OS(C)(=O)=O)c(C(=O)NCc2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl ethyl[(4S)-1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)-5-hydroxy-4-methoxypentyl]carbamate (30 g, 57.4 mmol) in AcCN (500 mL) at 0° C. was added TEA (48 mL, 344 mmol) followed by a dropwise addition of a solution of MsCl (22.37 mL, 287 mmol) in DCM (15 mL). The resulting mixture was stirred at 0° C. for 30 minutes, then diluted with H2O (˜100 mL) and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was used in the next step without further purification. LC-MS: 757.5 (M+1).
Reaction SMILES: N12CCN(CC1)CC2.Cl[C:10]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12](=[O:20])[C:11]=1[C:21]#[N:22].[N:23]1([C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CC(N(C)C)=O>[O:20]=[C:12]1[C:11]([C:21]#[N:22])=[C:10]([N:26]2[CH2:27][CH2:28][N:23]([C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[O:30])[CH2:24][CH2:25]2)[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2cccnc2[nH]c1=O
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2[nH]c1=O
Temperature: 110 °C
Yield: 51.1 %

Procedure:
1,4-Diazabicyclo[2.2.2]-octane (8.60 g, 77 mmol) was added to a solution of 4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (31) (7.9 g, 38 mmol) and piperazin-1-yl-thiophene-2-yl-methanone (11.30 g, 57 mmol) in dimethylacetamide at room temperature. The solution was heated at 110° C. overnight. The solution was cooled and poured into ice cold 10% NH4Cl solution. The solids formed were filtered, washed by cold water and dried under vacuum at room temperature to yield 7.1 g (51%) of 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (33) as white solids. MP 320° C.; 1H-NMR (DMSO-d6): δ 3.69 (m, 4H), 3.90 (m, 4H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.30 (dd, J=4.4, 8.0 Hz, 1H), 7.49 (d, J=3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.20 (dd, J=2.0, 8.0 Hz, 1H), 8.60 (d, J=3.2 Hz, 1H), 12.20 (S, 1H); EIMS: 366 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>CO.CC(OC)(C)C.Cl[Pd]Cl>[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)c1ccc(F)cc1Cl
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)c1ccnc(-c2ccc(F)cc2Cl)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 43.4 %

Procedure:
Methyl 2-chloroisonicotinate (3.5 g, 20.40 mmol), 2-chloro-4-fluorophenylboronic acid (3.91 g, 22.44 mmol), potassium carbonate (2.114 g, 15.30 mmol) and PdCl2 (dppf) (0.443 g, 0.61 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a dark-brown solid. The solid was dissolved in MTBE and stirred for 15 minutes, then filtered. The MTBE layer was treated with hydrogen chloride (4 M in dioxane, 5.10 mL, 20.40 mmol) and stirred for 1 h at room temperature. The precipitate was collected by filtration. Methyl 2-(2-chloro-4-fluorophenyl)isonicotinate (2.350 g, 38.1%) was obtained as a light yellow solid. 1H NMR (400 MHz, cdcl3) δ 4.13 (s, 3H), 7.24-7.33 (m, 1H), 7.36 (d, 1H), 7.82-8.03 (m, 1H), 8.34 (s, br., 1H), 8.56 (s, br., 1H), 9.08 (s, br., 1H). MS m/z 266 (M+H)+
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)=[CH2:2].[Li]CCCC.[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[CH:19]1([C:23]([C:13]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=3)[N:10]=[CH:11][N:12]=2)=[O:22])[CH2:20][CH2:21]1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(-n2cncn2)cc1
Agent: [Li]CCCC
Product: C=Cc1ccc(-n2ncnc2C(=O)C2CC2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy N-methylcyclopropoxide in THF (0.82 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (420 mg, 30%): mp 90-91° C.; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 6.75 (dd, J=16.3, 10.7 Hz, 1H), 5.81 (d, J=16.3 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 3.22 (m, 1H), 1.27 (m, 2H), 1.18 (m, 2H); ESIMS m/z 240.18 ([M+H]+); IR (thin film) 2922, 1630 cm−1.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:29]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23](C(=O)C)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1>[CH2:31]([CH:30]([N:29]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[C:3]([OH:4])=[O:2])[CH2:33][CH3:34])[CH3:32]
Reactant: CCC(CC)n1c(C(=O)OC)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(CC)n1c(C(=O)O)cc2cnc(Nc3ccc(N4CCNCC4)cc3)nc21
Reaction time: 36 h
Yield: 67.7 %

Procedure:
To a solution of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester (16 mg, 0.034 mmol) in THF (1.5 mL) is added 2 N LiOH aqueous solution (1 mL). The reaction mixture is stirred for 36 h and concentrated in vacuo. The residue is purified by preparative HPLC to give 9.4 mg of 7-(1-ethyl-propyl)-2-(4-piperazin-1-yl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].Br[CH2:13][C:14]([OH:16])=[O:15]>CC(CC)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:13][C:14]([OH:16])=[O:15]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(O)CBr
Solvent: CCC(C)=O
Product: O=C(O)COc1ccc2ccccc2c1
Temperature: 50 °C
Yield: 75.2 %

Procedure:
In a two-neck flask provided with a condenser and placed under an inert atmosphere, 2-naphthol (3.0 g, 20 mmol) is dissolved in 95 mL of methylethylketone (MEK) in the presence of soda (40 g, 93 mmol), and then heated to 50° C. for 30 minutes. 2-bromoethanoic acid (5.76 g, 41 mmol) dissolved in 23 mL of MEK is added dropwise under hot conditions. The heating is maintained for a further 4 hours. The reaction medium is cooled to room temperature and then filtered. The solid collected by filtration is taken up in a mixture of ethyl acetate and of 1N HCl in water. Both phases are separated and the aqueous phase is extracted once with ethyl acetate. The organic phases are collected, dried on magnesium sulfate, filtered and concentrated until the first crystals appear. Heptane is added (about 20% of the remaining volume), and the formed precipitate is recovered, rinsed with heptane and dried until it has constant weight in order to obtain 3.04 g (72%) of (naphthalen-2-yloxy)acetic acid as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=5)[N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C(Cl)Cl>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH3:39][S:36]([C:33]1[CH:34]=[CH:35][C:30]([C:29]2[N:23]3[C:24]([CH:25]=[N:26][C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][CH:16]=4)=[N:22]3)=[CH:27][CH:28]=2)=[CH:31][CH:32]=1)(=[O:37])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc(C5CCNCC5)cc4)nn23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To a round bottom flask 4-{4-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl}-piperidine-1-carboxylic acid tert butyl ester (7-% pure, 0.762 g, 0.00135 mol) and 3.0 M Trifluoroacetic acid in DCM (10 mL, 0.030 mol) were added. The mixture was stirred at room temperature for 1 h then the solvent was removed by rotary evaporation. The crude product was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give [7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-piperidin-4-yl-phenyl)-amine; compound with trifluoro-acetic acid as a yellow fluffy solid (0.06 g, 10%). LCMS (E/I+) 448.1 (M+H). NMR 1H (CDCl3/DSMO-d6)-9.97 (s, 1H), 9.50 (s, 1H), 8.41 (d, 2H, J=8.52 Hz), 8.20 (s, 1H), 8.02 (d, 2H, J=8.51 Hz), 7.67 (d, 2H, J=8.67 Hz), 7.20 (d, 2H, J=7.6 Hz), 7.11 (d, 1H, J=4.90 Hz), 6.88 (d, 1H, J=4.88 Hz), 3.54 (d, 2H, J=12.06 Hz), 3.14 (s, 3H), 3.02 (m, 3H), 2.59 (m, 2H), 2.05 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+].[Cl-].[Cl-].[Ca+2]>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCCCBr
Reactant: N#Cc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1
Temperature: 60 °C
Yield: 83.6 %

Procedure:
15.06 g (0.067 mol) of 4-(4-cyanophenylazo)phenol, 14.99 g (0.067 mol) of ethyl 6-bromo-hexanoate (Aldrich, 99%) and 11.76 g (0.085 mol) of oven dried K2CO3 were mixed in a 250 mL one-neck round flask fitted with a magnetic stirring bar. 160 mL of dry acetone was added, the flask was closed with a reflux condenser protected on the top with a CaCl2-drying tube and the stirred solution was refluxed on an oil bath at 60° C. for 72 h. After cooling the flask was transferred to a Rotavapor and the acetone was removed by rotary evaporation. The resulting solid mixture was added 200 mL of hot water and stirred. The aqueous mixture was allowed to cool and then filtered by suction from a water aspirator. The undried filtercake was transferred to a 500 mL Erlenmeyer flask, 300 mL of ethanol was added and the content of the flask brought to boiling. After cooling 20.46 g (yield 83%) of ethyl 6-[4-(4-cyanophenyl-azo)phenoxy]-hexanoate was filtered off. The crude ethyl 6-[4-(4cyanophenylazo)phenoxy]-hexanoate was recrystallized from 750 mL of ethanol and then repeatedly from 650 mL of ethanoL After vacuum drying at 50° C. for 20 h a final yield of 17.21 g (70%) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)[C:7]=2[C:8]1=[O:22]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Yield: 43.8 %

Procedure:
A solution of (R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (83 mg, 0.179 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (111 mg, 0.536 mmol), and bis(triphenylphosphine)palladium chloride (12.53 mg, 0.018 mmol) in dioxane (2 mL) and saturated aq Na2CO3 (2 mL) was heated at 120° C. for 30 min. After filtering off the solid, the solvent was removed, and the residue was dissolved in MeOH and DCM and was purified by preparative HPLC. The fractions were collected and the solvent was stripped to dryness via rotary evaporation to yield the title compound (40 mg, 44%). [M+H] calc'd for C26H31FN6O4, 511. found, 511.
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:14])[C:8]2[NH:9][CH:10]=[N:11][C:12]=2[N:13]=1)(=O)C.ClC(Cl)C.C(C([C@:24]([C:48](=[O:55])C1C=CC=CC=1)([C@:26](C(=O)C1C=CC=CC=1)([C@H:28]([CH2:30][O:31]C(=O)C1C=CC=CC=1)[OH:29])[OH:27])O)=O)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>N1C=CC=CC=1.C(Cl)Cl>[CH:10]1[N:11]([C@H:30]2[O:31][C@@H:24]([CH2:48][OH:55])[C@H:26]([OH:27])[C@@H:28]2[OH:29])[C:12]2[NH:13][C:5]([NH2:4])=[N:6][C:7](=[O:14])[C:8]=2[N:9]=1
Reactant: CC(=O)Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: CC(=O)C(=O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@H](O)COC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1nc(=O)c2ncn([C@H]3O[C@@H](CO)[C@H](O)[C@@H]3O)c2[nH]1
Temperature: 25 °C

Procedure:
N2-Acetylguanine (4.125 g, 21.35 mmol) was suspended in pyridine (50 mL) at 80° C. for 25 min. and then pyridine was evaporated under high vacuum. The same, procedure was repeated once. The obtained material was dried under vacuum overnight and silylated by heating with excess of HMDS (50 mL), pyridine (10 mL) and TMSCl (150 mL) under argon for 2.5 hours. After the reaction mixture was cooled to RT, the solvents were evaporated under vacuum. The residual HMDS and pyridine were coevaporated with xylene (2×40 mL). The silylated base was suspended in dichloroethane (70 mL) and combined with dichloroethane (182 mL) solution of 1-acetyl-2,3,5-O-tribezoyl-L-ribose (9.71 g, 19.22 mmol). The obtained suspension was stirred under argon at reflux temperature for 10 min. and dichloroethane (35 mL) solution of TMS-triflate (4.50 mL, 23.276 mmol) was added dropwise (20 min). The obtained reaction mixture was stirred under reflux for 1.5 h, cooled to RT and diluted with methylene chloride (500 ml). The organic solution was washed with cold NaHCO3 (5% aq., 2×150 mL), brine (150 mL), dried. (Na2SO4) and evaporated to dryness. The reaction mixture was purified by flash chromatography (400 g of silica gel, eluent: 28% EtOAc, 2% EtOH in CH2Cl2, v/v) to give 5.60 g (46%) of N2-Acetyl-2′,3′,5′-O-tribenzoyl-∃-L-guanosine 5.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([NH:19][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCCN
Product: CCCCCCC/C=C/C(=O)NCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and hexylamine as starting materials to give the aimed compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:25][C:24]([NH2:27])([CH3:26])[CH2:23][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 48 h
Yield: 94.1 %

Procedure:
A stirred solution of 4-chloro-3-nitroquinoline (2.08 g, 10.0 mmol) in 20 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (2.79 mL, 20.0 mol) and 1,2-diamino-2-methylpropane (1.15 mL, 11.0 mmol). After stirring for 2 d, the reaction mixture was diluted with 100 mL of CHCl3 washed with H2O (3×50 mL) and brine (50 mL). The organic portion was dried over Na2SO4 and concentrated to give 2-methyl-N1-(3-nitroquinolin-4-yl)propane-1,2-diamine (2.45 g) as a bright yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH2:24][CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH2:24]([C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1)[CH3:25]
Reactant: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-ethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.89) (0.30 g, 0.739 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.179 g, 0.813 mmol) according to the general procedure VI. Obtained as a white solid (0.050 g, 16%). MS (ISP) 420.1 [(M+H)+]; mp 74° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[CH3:20][S:21]([C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1)(=[O:23])=[O:22]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:28][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][N:26]=3)[CH2:30][CH2:31]2)=[O:10])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3ncc(S(C)(=O)=O)s3)CC2)c1
Yield: 36 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a yellow crystalline solid (yield 36%). MS (m/e): 500.1 (M+H+, 100%), 517.2 (M+NH4+, 69%).