Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(F)cc2)c(C)[nH]1
Yield: 76 %

Procedure:
4-[2-(4-Fluorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (111) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-Fluorophenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/RT. Purification: recrystallization from ether/pentane. Yield: 76%. 1H (CDCl3, 400 MHz): δ 10.5 (NH, broad s), 7.31 (1H, s), 7.22 (2H, dd), 6.99 (2H, dd), 4.36 (2H, q), 4.06 (2H, s), 2.58 (3H, s), 1.39 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 194.1, 163.0, 161.5, 160.6, 141.0, 131.1, 130.7, 121.5, 120.5, 116.9, 115.4, 115.2, 61.0, 45.9, 14.4, 14.0 ppm. LC/MS: 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[N:12]1C=NC=N[CH:13]=1.N1CCCCC1>CO>[N:1]1[C:2]2[C:3](=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=2)[C:4]([OH:5])=[N:12][CH:13]=1
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: c1ncncn1
Solvent: C1CCNCC1
Solvent: CO
Product: Oc1ccc2ncnc(O)c2c1
Temperature: 0 °C
Yield: 72.3 %

Procedure:
A mixture of 2-amino-5-hydroxybenzoic acid (19.64 g, 128 mmol), 1,3,5-triazine (15.6 g, 192 mmol), and piperidine (9 mL, 92.4 mmol) were heated to 60° C. in methanol (60 mL) for 2 hours. After cooling to 0° C., the mixture was filtered. The solid was washed with cold methanol and dried under high vacuum to provide the product (15 g, 72%) as white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1
Reactant: OCCCc1ccncc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: OCCCC1CCNCC1

Procedure:
4-Pyridinepropanol (10.0 g, 73 mmol) was dissolved in glacial acetic acid (50 mL). 10% Palladium on carbon (1.1 g) was added and the mixture hydrogenated under 50 psi hydrogen gas for 6 days. The mixture was filtered through Celite and the solvent removed by rotary evaporation. The crude product 3-piperidin-4-yl-propan-1-ol (acetic acid salt) was used as obtained. 1H NMR (500 MHz, CDCl3) □ 6.3 (br), 3.65 (2H, t), 3.36 (2H, m), 2.79 (2H, dt), 2.01 (3H, s), 1.85 (2H, m), 1.7-1.3 (7H, m).
Reaction SMILES: [O:1]=[S:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([N:18]3[CH2:23][CH2:22][N:21]4[CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=[C:20]4[CH2:19]3)=[N:6][C:5]=2[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C=O>[N:39]1([C:27]([C:25]2[N:26]=[C:20]3[CH2:19][N:18]([C:7]4[N:8]=[C:9]([NH:11][CH:12]5[CH2:13][CH2:14][O:15][CH2:16][CH2:17]5)[C:10]5[S:2](=[O:1])[CH2:3][CH2:4][C:5]=5[N:6]=4)[CH2:23][CH2:22][N:21]3[CH:24]=2)=[O:28])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cn2c(n1)CN(c1nc3c(c(NC4CCOCC4)n1)S(=O)CC3)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cn2c(n1)CN(c1nc3c(c(NC4CCOCC4)n1)S(=O)CC3)CC2)N1CCOCC1
Temperature: 25 °C

Procedure:
50 mg of 7-[5-oxo-4-(tetrahydropyran-4-ylamino)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (see 13.1) are placed in 2 ml dimethylformamide, then 66 μl diisopropylethylamine and 54.2 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min a suspension of 11.4 mg morpholine in 300 μl dimethylformamide is added. The reaction mixture is stirred at ambient temperature until there is no further reaction, and the product is purified directly by preparative HPLC (method B). 40 mg of Example 48 are obtained as a solid. Analytical HPLC-MS (method D): RT=0.79 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.C(OC([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=O)(C)(C)C>>[CH:14]1([N:8]2[C:6]3[N:7]=[C:2]([NH:38][C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]5)=[CH:37][CH:36]=4)[N:3]=[CH:4][C:5]=3[C:10]([C:11](=[O:13])[CH3:12])=[CH:9]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(=O)c1cn(C2CCCC2)c2nc(Cl)ncc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Product: CC(=O)c1cn(C2CCCC2)c2nc(Nc3ccc(N4CCNCC4)cc3)ncc12

Procedure:
1-[7-cyclopentyl-2-(4-piperazin-1-yl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethanone is prepared from 1-(2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethanone and 4-(4-Aminophenyl)-piperazine-1-carboxylic acid tert-butyl ester using a method similar to that for the preparation of Example 202. [M+H+] 405.2.
Reaction SMILES: [Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([N+:26]([O-:28])=[O:27])[C:7](OS(C3C(C)=CC(C)=CC=3C)(=O)=O)=[CH:8][CH:9]=2)[O:4][C:3]=1[CH:29]([CH3:31])[CH3:30].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([N+:26]([O-:28])=[O:27])[C:7]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[CH:8][CH:9]=2)[O:4][C:3]=1[CH:29]([CH3:30])[CH3:31]
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2ccc3c(=O)c(Br)c(C(C)C)oc3c2[N+](=O)[O-])c(C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CNc2ccc3c(=O)c(Br)c(C(C)C)oc3c2[N+](=O)[O-])cc1
Temperature: 130 °C

Procedure:
To a solution of 2,4,6-trimethyl-benzenesulfonic acid 3-bromo-2-isopropyl-8-nitro-4-oxo-4H-chromen-7-yl ester (1.906 g, 3.5 mmol) in dry toluene (18 ml) in a 20 ml capacity microwave tube is added p-methoxybenzylamine (0.69 ml, 5.26 mmol). The mixture is heated at 130° C. under microwave irradiation for 90 minutes and then at 140° C. under microwave irradiation for a further 30 minutes. Water (40 ml) is added, and the mixture is extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts are combined, washed with saturated brine (50 ml), dried (MgSO4), filtered and evaporated. The crude product is purified by chromatography on silica gel using cyclohexane-ethyl acetate (8:1) as eluant. The product-containing fractions are evaporated under reduced pressure, and the residue is triturated with diethyl ether to give a pale yellow solid.
Reaction SMILES: C(Br)C1C=CC=CC=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[O:21][CH3:22].[C-:23]#[N:24].[K+].O>CN(C=O)C>[CH3:22][O:21][C:12]1[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[CH2:10][C:23]#[N:24]
Reactant: [C-]#N
Reactant: COc1ccc(CBr)c(OC)c1OC
Agent: BrCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CC#N)c(OC)c1OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Phosphortribromide (6.83 g, 25.22 mmol) was added dropwise to a stirred solution of 2,3,4-trimethoxybenzyl alcohol (10 g, 54.44 mmol) in dichloromethane (100 ml), cooled at 0° C. After 30 min of vigorous stirring, the reaction mixture was slowly quenched with 100 g of ice-water. The dichloromethane layer was separated and the aqueous layer was further extracted with dichloromethane (2×100 ml). The combined extracts were twice washed with a saturated solution of sodium chloride (2×150 ml). The organic solution was dried over magnesium sulphate and evaporated to give 10 g (yield 76%) of the benzylbromide 2 as a colourless oil. As soon as isolated, the benzyl bromide compound was directly used for the next step. In fact the compound degradated after one night even at +4° C. The obtained 1-bromomethyl-2,3,4-trimethoxybenzene oil was treated with KCN (6.52 g, 100 mmol) in dry DMF (30 ml), at 0° C. and under nitrogen atmosphere. The obtained mixture was stirred for 3 g at 0° C. and 1 h at 60° C. The cooled reaction mixture was poured into water (80 ml) and extracted with diethylether (3×150 ml). The crude benzylcyanid was chromatographed on silica (diethylether/petroleumether: 1/3) to give 2,3,4-trimethoxyphenyl-acetonitrile as a white crystalline material (Yield: 6.8 g; 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13](N)=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.[ClH:34].N([O-])=O.[Na+]>CC#N.O.Cl[Cu]>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13]([Cl:34])=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1
Reactant: Cl
Reactant: COC(=O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
To a solution of 2-[6-amino-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester (14.7 g, 27.7 mmol) in a mixture of MeCN and H2O (120 mL/120 mL), concentrated HCl (25 mL) was added. The reaction mixture was cooled down to 0-5° C. and a solution of NaNO2 (2.9 g, 42.0 mmol) in water (3 mL) was added dropwise. The reaction mixture was stirred at 0-5° C. for 40 min and CuCl (I) (27 g, 272.7 mmol) was added at once. The reaction mixture was heated at 50° C. for additional 3 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (200 mL) and brine (100 mL). The organic phase was dried over MgSO4 and evaporated to give the product (14.5 g, 95%) as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 6.98 (dd, J=6.1, 1.6 Hz, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.48 (t, J=7.7 Hz, 1H), 2.20-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.6, 153.5, 142.2, 141.0, 138.9, 129.7, 125.0 (q, 3JCF=3.6 Hz), 124.8, 124.0 (q, 1JCF=271.6 Hz), 126.6 (q, 1JCF=278.8 Hz), 121.4, 114.0, 67.3 (q, 1JCF=35.4 Hz), 52.2, 49.3, 40.8, 34.0, 28.3, 28.0, 18.5.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][CH:2]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[C:3]([O:5][CH3:6])=[O:4])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)C(N)c1cccs1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(NC(=O)c1ccc(F)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of methyl α-amino-2-thiophene acetate (1.48 g), 4-fluorobenzoyl chloride (1.64 g) and sodium hydrogen carbonate (2.89 g) in methylene chloride (20 ml) and water (20 ml) was stirred at room temperature overnight. The organic layer was collected, washed with water and brine, and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate-hexane to obtain methyl α-(4-fluorobenzoylamino)-2-thiophene acetate (2.40 g) as colorless powder.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][C:50]=1[C:59]1[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=1>CN(C=O)C>[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][C:50]=1[C:59]1[CH:60]=[C:61]([NH:65][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=1
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3ccccc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.1 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.068 mmol) and HATU (0.029 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-naphthalen-2-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.010 g of product in 36% yield: LCMS (ESI) m/z 408 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH2:25][CH3:26])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].[Br:33]Br>C(O)(=O)C.O>[Br:33][CH:25]([C:10]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:27])[C:14]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=1)[CH3:26]
Reactant: CCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cl)cccc1Cn1c(C(C)Br)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
In a 100 mL round bottom flask combined 4-[(3-chloro-2-methylphenyl)methyl]-5-ethyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (4.1 g, 10.13 mmol) (Example 75) and sodium acetate (1.246 g, 15.19 mmol) in acetic acid (30 mL). Bromine (0.782 mL, 15.19 mmol) in acetic acid (5 mL) was added dropwise over ˜3 min. The red colored reaction was stirred at room temperature for 16 hr. LC/MS indicated complete conversion to product. This reaction mixture was diluted with water (150 mL), producing a gummy yellow residue. The mixture was extracted with chloroform (100 mL), then concentrated to a thick yellow oil. This oil was triturated from ether (150 mL), to provide, after sonication a yellow solid that is consistent with 5-(1-bromoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (4.52 g, 9.34 mmol, 92% yield). The proton NMR is consistent for the desired product. LC/MS m/z MH+=484 (theoretical), found=484.9, 1H NMR (400 MHz, CHLOROFORM-d) S ppm 1.97 (d, J=6.57 Hz, 3H) 2.51 (s, 3H) 3.52-3.64 (m, 4H) 3.71-3.84 (m, 4H) 4.53-4.65 (m, 1H) 5.43 (d, J=17.43 Hz, 1H) 5.95 (d, J=17.43 Hz, 1H) 6.38 (d, J=7.83 Hz, 1H) 7.06 (t, J=8.08 Hz, 1H) 7.34 (d, J=7.83 Hz, 1H)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>C1COCC1>[O:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: OC1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(COC2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
Add sodium bis(trimethylsilyl)amide (2.8 mL, 5.61 mmol, 2M solution in THF) to a solution of tetrahydro-pyran-4-ol (572 mg, 5.61 mmol) in anhydrous THF (20 mL) and stir for 30 min. Add a solution of 4-bromomethyl-benzonitrile (1 g, 5.1 mmol) in anhydrous THF (5 mL) and stir the resulting mixture overnight at room temperature. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with cyclohexane/EtOAc (98:2 to 1:1 gradient) to obtain the desired intermediate as a white solid (845 mg, 76%). GC-MS m/z: 217 (M+);
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([NH2:13])[NH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[CH:18][CH:17]=1>C(O)(=O)C>[CH2:1]([C:8]1[N:9]=[C:10]2[NH:13][C:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=3)=[CH:23][C:24](=[O:25])[N:11]2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: Nc1nc(Cc2ccccc2)n[nH]1
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(=O)n3nc(Cc4ccccc4)nc3[nH]2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
A mixture of 5-benzyl-2H-1,2,4-triazol-3-amine (174 mg, 1.00 mmol, 1.00 equiv), acetic acid (3 mL), and ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (228 mg, 1.10 mmol, 1.10 equiv) was stirred overnight at 110° C. and then concentrated to dryness. The resulting solid was washed with 5 mL MeOH and collected by filtration. The solid was dissolved in 10 mL of NH4OH (aq.) and filtered. The filtrate was adjusted to pH 6 with HOAc. The resulting solid was collected by filtration and washed with water. The solid was dried to get 26 mg (8%) of 2-benzyl-5-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a white solid.
Reaction SMILES: [C:1](=[O:13])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2][CH:3](Cl)[CH3:4].[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O-:27])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15].[K+].[I-].[K+]>CN(C=O)C>[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O:27][CH:3]([O:2][C:1]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:13])[CH3:4])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CC(Cl)OC(=O)Oc1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(=O)Oc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 96 h

Procedure:
1-Chloroethyl phenyl carbonate (prepared according to Synthesis 1986, 627) (2.21 g, 11 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 10 mmol) and potassium iodide (0.17 g, 1 mmol) in dry DMF. After stirring at 50° C. for 6 hours and at room temperature for 4 days the solvent was removed at reduced pressure. The residue was suspended in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 7.3 g. Purity by HPLC: 98%. 1H-NMR (DMSO-d6): delta=1.68 (N(CH3)COCH3); 1.74 (CHCH3); 2.05 (NCOCH3); 2.97 (NCH3); 7.05 (CH); 7.25-7.52 (arom.); 10.14 ppm (NH).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31].[H-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]([Br:41])=[CH:37][N:36]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:41][C:38]1[CH:37]=[N:36][C:35]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[N:40][CH:39]=1
Reactant: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Reactant: Clc1ncc(Br)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCOc2ncc(Br)cn2)c1Oc1ccccc1OC
Temperature: 75 °C
Yield: 44.9 %

Procedure:
Ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2]bipyrimidinyl-4-yl]-amide (89 mg) was dissolved in THF (10 ml). Sodium hydride (60 mg) and 2-chloro-5-bromo-pyrimidine (100 mg) were added and the mixture was heated to 75° C. for 48 h, then poured onto water, acidified with solid citric acid and the precipitate was filtered off. The crude material was purified by crystallization from methanol to give ethanesulfonic acid [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (54 mg) as a white powder. LC-MS: tR: 4.23, [M+H]+: 605.90.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18](=[O:29])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].[CH3:30][O:31][C:32]1[N:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][C:36](O)=[CH:35]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:29])[NH:19][C@H:20]1[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][O:28][C:36]2[CH:37]=[N:38][C:39]3[C:34]([CH:35]=2)=[N:33][C:32]([O:31][CH3:30])=[CH:41][CH:40]=3)[CH2:24][CH2:25]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc2ncc(O)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(OCC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)cc2n1
Temperature: 30 °C
Reaction time: 14 h

Procedure:
Diethyl azodicarboxylate (3.96 g, 22.72 mmol, 3.0 eq) is added at room temperature to a stirred solution of [trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (1.84 g, 7.57 mmol, 1.0 eq), 6-methoxy-[1,5]naphthyridin-3-ol (1.80 g, 10.22 mmol, 1.35 eq) and triphenylphosphine (5.96 g, 22.72 mmol, 3.0 eq) in tetrahydrofuran (70 mL). After 14 hours stirring at 30° C., tetrahydrofuran is evaporated and the resulting crude product is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 6:1, v/v) to afford {trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as an off-white solid (1.65 g, 53.5% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)=[N:4]1)[CH3:2].[CH3:36][CH:37]([CH3:41])[C:38](Cl)=[O:39]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:29]2[CH:30]=[CH:31][C:32]([NH:33][C:38](=[O:39])[CH:37]([CH3:41])[CH3:36])=[CH:34][CH:35]=2)=[N:4]1)[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)c(-c2ccc(NC(=O)C(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
To a cloudy orange mixture of 4-(1-ethyl-4-{2-[4-(1-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)aniline (280 mg, 0.61 mmol) in dry CH2Cl2 (6 mL) was added TEA (253 uL, 1.82 mmol), DMAP (4 mg, 0.03 mmol) and 2-methylpropanoyl chloride (77 uL, 0.73 mmol). The reaction was stirred for 15 min at room temperature, quenched with water and diluted with CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2 followed by 1% MeOH in CH2Cl2 and the combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by Gilson reverse phase HPLC (MeCN/H2O with 0.1% TFA). The clean fractions were neutralized with aqueous NaHCO3, extracted with three portions of CH2Cl2 followed by 1% MeOH in CH2Cl2, dried (Na2SO4), filtered and concentrated under reduced pressure to give 139 mg (43%) of the title product as a yellow solid. ESMS [M+H]+: 533.4.