Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COc1cccc(CN)c1
Solvent: ClCCl
Product: COc1cccc(CNC(=O)c2c(Cl)ncnc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (587 mg, 2.78 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (2.5 ml) and TEA (400 μl, 2.87 mmol) was added. To this solution, (3-methoxyphenyl)methanamine (379 mg, 2.76 mmol) in 3 ml DCM was added dropwise and the mixture was stirred for 30 min at room temperature. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (10% to 30%, hexane-ethyl acetate) to obtain 534 mg (61% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([CH2:17][CH3:18])[N:11]=1>C(OCCO)C>[CH2:17]([C:12]1[N:13]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[CH:15]=[C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[N:11]=1)[CH3:18]
Reactant: CCc1nc(Cl)cc(Cl)n1
Reactant: Nc1cccc(O)c1
Solvent: CCOCCO
Product: CCc1nc(Nc2cccc(O)c2)cc(Nc2cccc(O)c2)n1
Reaction time: 5 h

Procedure:
After dissolving 3-aminophenol (1.09 g, 10.0 mmol) in 2-ethoxyethanol (5.0 mL), 4,6-dichloro-2-ethylpyrimidine (0.89 g, 5.0 mmol) was added and stirring carried out for 5 hours at 130° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([OH:7])[CH3:6].C(Cl)(=O)C.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]>C(Cl)(Cl)Cl.O>[CH3:6][C:5]([C:17]1[CH:16]=[CH:15][C:14]([O:19][CH3:20])=[C:13]([Cl:12])[CH:18]=1)=[O:7]
Reactant: COc1ccccc1Cl
Reactant: CCO
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
Anhydrous aluminum chloride (281 g, 2.104 mol) and 1 L of ethanol-free chloroform were maintained at 0° C. with an ice bath while a solution of acetyl chloride (162 g, 2.28 mol) in 300 mL of chloroform was added over 25 minutes. To this solution was added 2-chloroanisole (250 g, 1.75 mol) in 250 mL of chloroform over 1 hour. The solution was stirred at room temperature for 16 hours and was poured into a mixture of ice and water. The phases were separated and the aqueous phase was extracted with dichloromethane and combined with the original organic phase. The combined organics were dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford a solid which was crystallized from dichloromethane/hexane to give 3-chloro-4-methoxyacetophenone (246 g, 76%) which was used directly in the next step without further purification.
Reaction SMILES: BrB(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[C:10]([F:14])[C:11]=1[O:12]C.[CH3:20]O>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([CH:15]([CH3:19])[C:16]([O:18][CH3:20])=[O:17])[CH:9]=[C:10]([F:14])[C:11]=1[OH:12]
Reactant: CO
Reactant: COc1c(F)cc(C(C)C(=O)O)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C(C)c1cc(F)c(O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
tribromoborane (7.37 mL, 77.99 mmol) was added dropwise to 2-(3,5-difluoro-4-methoxyphenyl)propanoic acid (Intermediate 21-4; 2.81 g, 13.00 mmol) in dichloromethane (96 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 1 hour. The reaction mixture was added dropwise to methanol (26.3 mL, 649.92 mmol) (—care reaction is vigorous and exothermic—MeOH kept in ice bath) and the mixture was stirred for a further 20 minutes. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with saturated NaHCO3 (50 mL) and water (50 mL). The organic layer was dried with MgSO4 and evaporated to afford desired product methyl 2-(3,5-difluoro-4-hydroxyphenyl)propanoate (2.490 g, 89%).
Reaction SMILES: [CH2:1]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:19]([O:23][CH2:24][CH2:25][NH2:26])=[C:20]([Br:22])[CH:21]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>C1COCC1>[CH3:48][O:47][C:45](=[O:46])[NH:26][CH2:25][CH2:24][O:23][C:19]1[C:20]([Br:22])=[CH:21][C:16]([C:14](=[O:15])[NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:17][C:18]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=1
Reactant: COC(=O)Cl
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCN)c(-c2cccc(C(F)(F)F)c2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCNC(=O)OC)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 0.25 h
Yield: 861.4 %

Procedure:
To a solution of 6-(amino-ethoxy)-5-bromo-3′-trifluoromethyl-biphenyl-3 carboxylic acid dodecylamide (0.273 g, 0.48 mmol, 1 eq) in THF (6 mL) at 0° C. was added triethylamine (0.150 mL, 1.08 mmol, 2.25 eq) followed by methyl chloroformate (0.040 mL, 0.052 mmol, 1.11 eq). The reaction was stirred for 15 min, then poured into pH 7 buffer and extracted with Et2O. The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane ) to afford the title compound (0.282 g, 93%) as a white solid. mp 79.6-80.5° C. 1H NMR (DMSO-d6) δ 8.56 (bt, 1H); 8.12 (d, 1H); 7.88 (m, 3H); 7.79 (d, 1H); 7.70 (t, 1H); 7.02 (t, 1H); 3.54 (dd, 2H); 3.44 (s, 3H); 3.24 (dd, 2H); 3.08 (ddd, 2H); 1.48 (dd, 2H); 1.23 (m, 18H); 0.83 (t, 3H); IR (KBr) 3330, 2950, 2840, 1695, 1640, 1540, 1340, 1180, 1110, 920, 805 cm−1; mass spectrum [(+)MAT900], rm/z 629/631 (M+H)+; Anal. Calcd. for C30H40BrF3N2O4: C, 57.23; H, 6.40; N, 4.45, Found: C, 56.12; H, 6.29; N, 4.29.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:33][CH3:34])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH3:34])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (200 mg, 0.86 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-methylquinolin-2-amine hydrochloride SLA 28154 (234 mg, 0.86 mmol) at RT followed by a 2 N aq. LiOH solution (0.86 mL, 1.72 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with a mixture CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 21 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.40 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 39 as a yellow solid (20.0 mg, 5% yield).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[N:15][S:16][CH:17]=1)[C:10]([OH:12])=O.C[Si](CC(N)=O)(C)C.[NH2:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12>C(OCC)(=O)C.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[N:15][S:16][CH:17]=1)[C:10]([NH:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12)=[O:12]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csnn1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csnn1
Temperature: -5 °C
Yield: 42.3 %

Procedure:
Dimethylformamide (0.34 g.) was added to dry ethyl acetate (1 ml.), and then phosphorus oxychloride (0.72 g.) was added thereto under 10° C. The mixture was stirred at -5° C. to solidify. Dry ethyl acetate (10 ml.) was added thereto and 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (0.8 g.) was added to the mixture at 0° C., after which the resulting mixture was stirred for 30 minutes at the same temperature. On the other hand, trimethylsilylacetamide (4.9 g.) was added to a suspension of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.54 g.) in dry ethyl acetate (30 ml.), and the mixture was stirred for 1 hour at 40° C. to give a clear solution. To this solution was added dropwise at -20° C. the above-obtained ethyl acetate solution, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was post-treated according to a similar manner to that of Example 12 to give pale yellow powder of 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g.).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12.C(N(C(C)C)C(C)C)C.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34](ON1C(=O)CCC1=O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]([NH:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: Nc1cnn2c1NCCC2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.3 %

Procedure:
To a solution of 3-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine sulfuric acid salt (2.96 g) and N-ethyldiisopropylamine (2.59 g) in methylene chloride (70 ml) was added N-[2-(tert-butoxycarbonylamino)acetoxy]succinimide (2.72 g). The mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 6% methanol/chloroform to give 3-[2-(tert-butoxycarbonylamino)acetyl]amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (2.4 g) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([Si:20]([CH3:23])([CH3:22])[O:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: OCC1CCCNC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CCCNC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
To a solution of piperidin-3-ylmethanol (2.10 g, 0.018 mol) in CH2Cl2 (20 mL) is added triethylamine (5.53 g, 0.0547 mol) followed by t-butyldimethylchlorosilane (4.127 g, 0.0275 mol) and the reaction mixture is stirred at room temperature. After 24 hours, the reaction mixture is washed with water, saturated solution of NaHCO3, and brine. The combined organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) over a gradient using 0-10% MeOH in dichloromethane to afford the title compound (2.50 g, 60%). Mass spectrum (m/z): 231.2 (M+1).
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[CH3:15])[C:8]([C:4]1[C:3](=[O:18])[C:24]2[C:23](=[CH:22][CH:21]=[C:20]([CH3:19])[N:25]=2)[NH:26][CH:5]=1)=[O:17]
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Cc1ccc(N)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc2[nH]cc(C(=O)c3ccc(C)c(C)c3)c(=O)c2n1
Yield: 22 %

Procedure:
Experimental conditions analogous to those described for step 1 of Example 1 were used with 0.50 g (2.01 mmol) 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester, 0.22 g (2.01 mmol) of 6-Methyl-pyridin-3-ylamine, and 15 mL of diphenyl ether to yield 129 mg of 3-(3,4-Dimethyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:60].Cl>>[ClH:1].[ClH:30].[ClH:60].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:18][CH:17]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Yield: 93 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[(4-methylpiperazin-1-yl)methyl]phenyl amino}-1,5-naphthyridin-3-yl)ethanone (74 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.27 mmol) followed by formation of the dihydrochloride salt to afford the desired product (96 mg, 93%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.32 (s, 1H), 8.44 (d, J=9.1 Hz, 1H), 8.34 (d, J=9.1 Hz, 1H), 7.65 (d, J=7.6 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.31 (br s, 1H), 7.12 (br s, 1H), 4.26 (br s, 2H), 3.45 (br s, 8H), 2.97 (s, 3H), 2.80 (s, 3H); ESI MS m/z 520 [M+H]+; HPLC>99% (AUC), tR=9.37 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[N+:5]([O-])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:12][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][N:5]=1)(=[O:15])[CH3:14]
Reactant: COc1cc[n+]([O-])c(C)c1OC
Reactant: CC(=O)OC(C)=O
Product: COc1ccnc(COC(C)=O)c1OC
Reaction time: 1 h
Yield: 90 %

Procedure:
4.8 g (28 mmol) of 3,4-dimethoxy-2-methylpyridine 1-oxide are metered into 25 ml of acetic anhydride at 85° C. in the course of one hour, the mixture is stirred at the same temperature for one hour and concentrated completely in vacuo and the brown oily residue is distilled in a bulb type still under 1 Pa. 5.3 g (90% of theory) of 2-acetoxymethyl-3,4-dimethoxypyridine are obtained; b.p. 125°-130° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>CN(C=O)C.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>[CH:15]([C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1)=[CH2:16]
Reactant: OCc1cn(-c2cccc(Br)c2)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1cccc(-n2cnc(CO)c2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
Under an Ar atmosphere, a solution of [1-(3-bromo-phenyl)-1H-imidazol-4-yl]-methanol (3.0 g, 12 mmol) in DMF (90 ml) was successively treated with PdCl2(PPh3)2 (0.87 g, 0.1 mmol) and vinyltributylstannane (4.1 g, 13 mmol). The resulting mixture was heated to 60° C. for 8 h. After evaporation of the solvent the residue was stirred for 30 min with AcOEt (60 ml) and aqueous 10% KF solution. The organic phase was separated and the aqueous phase was extracted 3 times with AcOEt. The combined organic phases were dried (Na2SO4), concentrated and chromatographed [silica, elution with gradient CH2Cl2 to 40% (CH2Cl2/MeOH=9:1)] to yield the title compound as a colorless oil (1.2 g, 51%). MS: m/e=201 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:73][O:74][CH2:75][CH2:76]O.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:76][CH2:75][O:74][CH3:73])=[O:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)O)c[nH]4)c3)cc2)c1
Reactant: COCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOC(=O)CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoic acid (300 mg, 0.56 mmol) in 10 ml of anhydrous DMF were added HATU (255 mg, 0.67 mmol) and N,N-diisopropylethylamine (217 mg, 1.68 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 2-methoxyethanol (0.50 ml, 6.3 mmol). The mixture was heated at 66° C. for 1 hour, and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with ethyl acetate to give 2-methoxyethyl 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate as white solid. Yield: 215 mg, 65%.
Reaction SMILES: [NH2:1][C:2]([CH3:50])([CH3:49])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[N:11]=[C:10]2[C:17]1[N:22]=[C:21]2[C:23]([C:45]([O:47]C)=[O:46])=[CH:24][N:25]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]2=[N:19][CH:18]=1.[OH-].[K+]>O.O1CCOCC1>[NH2:1][C:2]([CH3:50])([CH3:49])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[N:11]=[C:10]2[C:17]1[N:22]=[C:21]2[C:23]([C:45]([OH:47])=[O:46])=[CH:24][N:25]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:20]2=[N:19][CH:18]=1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(C)c4ccc(OCCCC(C)(C)N)cc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OCCCC(C)(C)N)ccc21
Temperature: 25 °C
Yield: 102.4 %

Procedure:
A mixture of methyl 2-(5-(4-amino-4-methylpentyloxy)-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (100 mg, 0.15 mmol), potassium hydroxide (280 mg, 5 mmol) in 2.5 mL of water and 5 mL of 1,4-dioxane was heated to reflux for 90 min. The reaction mixture was cooled to room temperature, solvent evaporated, the residue diluted with H2O (25 mL) and the mixture acidified with 1N HCl to pH=7. The residue was extracted with EtOAc (100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-(5-(4-Amino-4-methylpentyloxy)-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid as yellow solid (100 mg, >100%) which was used to next step without further purification. LCMS: (M+H)+=651.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:20]=4[F:33])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][N:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[F:33][C:20]1[CH:21]=[C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([OH:4])[CH2:6][CH2:7]2)[C:12]2[N:13]([N:37]=[CH:38][N:39]=2)[C:14]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@@H](O)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (1 g), 6N hydrochloric acid (10 mL) and tetrahydrofuran (15 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 mL), sodium borohydride (0.11 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.085 g, 9%).