Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36](C([O-])=O)[N:35]=[CH:34]2.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.O>CS(C)=O>[F:29][C:19]1[CH:18]=[C:17]([C:10]2[N:9]=[C:8]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][N:35]=[CH:34]4)[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:47]4[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]4)[CH:6]=3)[N:11]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCCl
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCN(C)CC1
Temperature: 85 °C

Procedure:
A mixture of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.35 g, 0.55 mmol) and 4-methyl piperazine in DMSO (1.5 mL) was heated at 85° C. for 3 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound. The lower running spot was isolated and then taken up in CH2Cl2 (6 mL) and TFA (5 mL). The mixture was stirred for 2.5 h at RT. The volatiles were removed in vacuo to give a solid which was triturated with Et2O, filtered and dried under vacuum to give the desired product 2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-amine (0.111 g, 0.184 mmol, 33%). MS 604.5 (M+1). HPLC retention time 5.10 mins.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[C:32](O)(=[O:34])[CH3:33]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@@H:3]([CH3:31])[CH2:2][NH:1][C:32](=[O:34])[CH3:33])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CC(=O)O
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CC(=O)NC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 60 %

Procedure:
The procedure described in Example 1 was repeated using acetic acid and 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine to give the title compound in 60% yield; NMR spectrum (DMSO-d6) 1.40 (d, 3H), 1.80 (s, 3H), 3.40 (m, 1H), 3.62 (m, 1H), 4.85 (m, 1H), 5.30 (s, 2H), 7.23 (m, 2H), 7.30 (d, 1H), 7.36 (m, 1H), 7.57 (m, 2H), 7.71 (t, 1H), 7.87 (td, 1H), 8.12 (d, 1H), 8.22 (t, 1H), 8.49 (s, 1H), 8.58 (d, 1H), 10.00 (s, 1H); Mass Spectrum MH+ 478.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.S(Cl)([Cl:19])(=O)=O.O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[C:9]=2[Cl:19])[N:4]=1
Reactant: COc1ccc2nc(OC)cc(C)c2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C)c2c(Cl)c(OC)ccc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A 500 ml, four-necked round bottom flask equipped with a mechanical stirrer, condenser, thermowatch and addition funnel was charged with 2,6-dimethoxy-4-methylquinoline (9) (17.9 g, 0.09 moles) and glacial acetic acid (120 ml). The resulting solution was heated to 60° C., then a solution containing sulfuryl chloride (13.4 g, 0.01 moles) and glacial acetic acid (40 ml) was added over 20 minutes. Reaction temperature was held between 60-65° C. during this addition. The resulting solution was stirred for 1 hour at 60-65° C., then additional sulfuryl chloride (3.8 g, o,028 moles) in glacial acetic acid (10 ml) was added. The mixture was stirred an additional 30 minutes, then it was poured into 300 ml of water. The slurry was cooled to 5° C., the product removed by suction filtration, washed with water and air dried. Yield was 18.4 g (86%); mp=97-100° C.; purity by HPLC=89.7 area %.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:34])[S:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([NH:23][C:24](=[O:33])[C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])[CH2:21]O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:21][CH:20]([NH:23][C:24](=[O:33])[C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32])[C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([S:7][CH:6]([F:34])[F:5])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NC(CO)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Temperature: 45 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A portion of 0.37 g (3.1 mmol) of thionyl chloride was added to 1.20 g (2.75 mmol) of N-[1-[4'-[(difluoromethyl)thio][1,1-biphenyl]4-yl]-2-hydroxyethyl]-2,6-difluorobenzamide and 10 mL of toluene. The mixture was warmed to 45° C. for 3.25 h. An additional portion of 0.25 g (2.1 mmol) of thionyl chloride was added and the mixture was stirred for an additional 1 h. The mixture was cooled to 25° C. and the solvent removed under reduced pressure gave the product 1.18 g (96% yield) as an off-white solid. Chromatography on silica gel (eluted with ethyl acetate/hexanes, 1:2) afforded an analytical sample; m.p. 146-147° C. IR (Nujol): 3290, 1652, 1625, 1539, 1311, 1234, 1065, 1009, 818 cm31 1. 1H-NMR(CDCl3): δ3.96-4.08 (m, 2H), 5.62-5.68 (m, 1H), 6.65 (d, J=7.3 Hz, 1H), 6.86 (t, J=57 Hz, 1H), 6.95-7.02 (m, 2H), 7.30-7.48 (m, 3H), 7.50-7.67 (m, 6H).
Reaction SMILES: C([BH3-])#N.[Na+].[I:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[CH:13](=O)[CH2:14][CH3:15]>CO>[CH2:13]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([I:5])=[CH:7][CH:8]=1)[CH2:14][CH3:15]
Reactant: CCC=O
Reactant: Nc1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Sodium cyanoborohydride (0.63 g) was added to a solution of 4-iodoaniline (2.2 g) and propionaldehyde (0.72 ml) in methanol (15 ml) whilst under an atmosphere of argon. The mixture was stirred at ambient temperature for 72 hours. Sodium cyanoborohydride (0.005 mole) was added and the reaction mixture was stirred for further 48 hours. The pH of the reaction mixture was adjusted to 1 using 2N aqueous hydrocyloric acid. The mixture was filtered and the filtrate was evaporated to yield N-propyl-4-iodoaniline as a solid (1.4 g), NMR: 0.9(3H,t), 1.65(2H,m), 3.1(2H,m), 7.05(2H,d) and 7.67(2H,d).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)OC1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2.C(O)(=O)C>CO>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][CH:4]3[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]3)=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
1,4-Cyclohexanedione monoethylene ketal (3.90 g), 5-aminoindazole (2.66 g), and acetic acid (0.5 ml) were dissolved in methanol (50 ml), and a borane-pyridine complex (2.50 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr, was then cooled to room temperature, and was concentrated. The residue was dissolved in acetic acid-water (1:1, 50 ml), and the mixture was then stirred at 80° C. for 3 hr. The reaction mixture was concentrated to remove a major part of acetic acid. A saturated aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (3.21 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][CH2:14][C@H:15]([OH:26])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1)=[O:17])[CH3:12].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=3)[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:42]1[C:37]([N:34]2[C:30]3[N:31]=[CH:32][N:33]=[C:28]([O:26][C@@H:15]([CH2:14][O:13][CH2:11][CH3:12])[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=4)=[O:17])[C:29]=3[CH:36]=[N:35]2)=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(C)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (3.26 mL, 3.26 mmol) was added dropwise to a stirred solution of (S)-3-ethoxy-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate G1) (730 mg, 3.26 mmol) in anhydrous THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (866 mg, 3.26 mmol) in dry THF (3 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 3hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography eluting with EtOAc to afford (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxy-N-(5-methylpyridin-2-yl)propanamide (930 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, t), 2.29 (3H, s), 3.59-3.67 (2H, m), 4.06-4.17 (2H, m), 6.06-6.08 (1H, m), 7.47 (1H, dd), 7.53 (1H, dd), 8.00 (1H, dd), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.48 (1H, s), 8.62 (1H, dd), 8.63 (1H, s), 8.65 (1H, s); m/z (ESI+) (M+H)+=454.3; HPLC tR=1.97 min.
Reaction SMILES: [CH3:1][C@@H:2]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5]1.[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23]1>C(Cl)Cl>[CH3:1][C@@H:2]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:28]([CH:22]1[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23]1)=[O:29])[CH2:3][N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:9]1
Reactant: C[C@H](CN1CC=C(c2cccs2)CC1)Nc1ccccn1
Reactant: O=C(Cl)C1CC=CCC1
Solvent: ClCCl
Product: C[C@H](CN1CC=C(c2cccs2)CC1)N(C(=O)C1CC=CCC1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
A solution of the starting (R)-[1-methyl-2-(4-thiophen-2-yl-3,6-dihydro-2H-pyrid-1-yl)-ethyl]-pyrid-2-yl-amine (0.46 g, 1.5 mmol) in methylene chloride (20 ml) was cooled to 0° C., after which a solution of cyclohex-3-enecarbonyl chloride (0.222 g, 1.5 mmol) in methylene chloride (10 ml) was dropwise added under exclusion of moisture. The reaction mixture was stirred at ambient temperature overnight, then washed with 2.5N NaOH (10 ml). The separated organic layer was washed with brine (50 ml), dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Column chromatography on 50 g of silica gel with chloroform as eluant, followed by trituration in ether with the addition of ethanolic HCl gave 0.27g of the title compound as the dihydrochloride, m.p. 92°-6° C.
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1.Cl>O1CCOCC1>[N:1]1([N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH:15]=[CH:19][CH:18]=[CH:17]1
Reactant: NN1C(=O)c2ccccc2C1=O
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1n1cccc1
Temperature: 25 °C
Yield: 53205 %

Procedure:
To a stirred solution of 1,4-dioxane (50 mL) and N-aminophthalimide (5.0 g, 0.031 mmol) at rt was slowly added 2,5-dimethoxy tetrahydrofuran (15 g, 0.061 mmol). The resulting light yellow solution was heated to 100° C. for ˜16 h whereupon 5N HCl was carefully added at 100° C. giving a brown mixture. The mixture was allowed to cool room temperature, the solid thus separated was filtered and was rinsed with 1:3 of 1,4-dioxane in water. Drying afforded 3.5 g (54%) of the title compound as a white solid. LCMS (Condition D) m/z: 213 +ve.
Reaction SMILES: [CH2:1]([C:20]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Cl-:46].[Ca+2].[Cl-].Cl>C(Cl)Cl>[CH2:1]([C:20]([Cl:46])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCCC(O)(CCCCCCCCCC)CCCCCCCCCCCCCC
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCC(Cl)(CCCCCCCCCC)CCCCCCCCCCCCCC

Procedure:
One mole of n-nonadecyl-n-tetradecyl-n-decylcarbinol is added to 0.2 liters of methylene chloride and 0.32 moles calcium chloride. Approximately 1.5 moles of HCl gas is slowly bubbled through the solution. The product mixture is then washed with 1 liter of a 10% sodium carbonate solution. The organic layer is dried with magnesium sulfate and the methylene chloride is evaporated off to give n-nonadecyl-n-tetradecyl-n-decylmethylchloride.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[CH3:15][O:16][C:17]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:18]=1[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28]([S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[C:29]([C:31]3[C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:44])[CH:32]=3)=[CH:30][C:23]=12.O>ClCCl>[CH3:15][O:16][C:17]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:18]=1[CH2:19][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28]([S:45]([C:48]3[CH:49]=[CH:50][C:51]([CH3:54])=[CH:52][CH:53]=3)(=[O:47])=[O:46])[C:29]([C:31]3[C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:44])[CH:32]=3)=[CH:30][C:23]=12)[C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)=[O:12]
Reactant: COc1ccc(CNCc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)C(=O)Nc2ccc(OC(F)(F)F)cc2)c(OC)c1
Reaction time: 24 h

Procedure:
0.094 cm3 of 4-(trifluoromethoxy)phenyl isocyanate is added to a solution of 0.080 g of (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine in 6 cm3 of dichloromethane, under an argon atmosphere, at a temperature in the region of 20° C. The reaction medium is stirred at this same temperature for 24 hours. 2 cm3 of water are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluent), 0.150 g of 1-(2,4-dimethoxybenzyl)-1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-3-(4-trifluoromethoxyphenyl)urea is obtained, the characteristics of which are as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:29])[C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])[CH:13]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:29])[C:12]2[CH:13]=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])[CH:15]=[C:16]([O:18][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[Cl:30])[CH:17]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccccc1COc1cc(O)cc(C(=O)Nc2ccc([N+](=O)[O-])cn2)c1
Reactant: Clc1ccccc1CBr
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1cc(OCc2ccccc2Cl)cc(C(=O)Nc2ccc([N+](=O)[O-])cn2)c1
Temperature: 85 °C
Reaction time: 17 h

Procedure:
A solution of N-(5-nitropyridin-2-yl)-3-[(2-cyanobenzyl)oxy]-5-hydroxybenzamide (195 mg) in DMF (3 ml) was treated with Ag2CO3 (165 mg) and 2-Chlorobenzyl bromide (0.073 ml). Heated to 85° C. and stirred for 17 hours under Nitrogen. Allowed to cool to ambient temperature. Water (25 ml) added. Extracted with ethyl acetate (50 ml), washed with brine (25 ml), dried over MgSO4. Volatile material was removed by evaporation to give a solid, which was purified by flash chromatography on silica eluted with 0-5% ethyl acetate in dichloromethane to give the title compound (43 mg) as a solid, 1H NMR δ (d6-DMSO): 5.20 (s,2H), 5.33 (s, 2H), 6.96 (s, 1H), 7.40 (m, 5H), 7.57 (m,2H), 7.72 (m, 2H), 7.90 (d, 1H), 8.40 (d, 1H), 8.64 (dd, 1H), 9.22 (s, 1H), 11.50 (s,1H). LCMS rt=3.27 min (97.4%), ES+515.50 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH2:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>O.CO>[OH:31][C@@H:21]1[C@H:22]([OH:30])[C@@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH2:24][C@H:20]1[N:17]1[CH:16]=[N:15][C:14]2[C:18]1=[N:19][C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)=[N:12][C:13]=2[NH:32][CH2:33][CH:34]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)c1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)O)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution comprising 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 173 step 1) (0.4 g, 0.64 mmol) in water (3 ml) is treated with 1M KOH in MeOH (6 ml) and stirred at room temperature for 48 h. The solvent is removed in vacuo and the resulting crude product is dissolved in water (5 ml) and acidified to pH 3-4 with 1.5N HCl. The solution is extracted with EtOAc and the organic portion is dried over sodium sulphate and concentrated in vacuo. Purification by chromatography on silica eluting with 5% MeOH in chloroform affords the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]>C(O)C.[Pd]>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: COCC#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: COCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Yield: 65 %

Procedure:
The product of Example 25, Step B, 3,4-difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]amino]benzoic acid, was hydrogenated in absolute ethanol in the presence of 5% Pd/C as above in Example 1, Step D. The resulting crude solid was purified by filtration through a plug of silica gel (50% EtOAc/hexanes as eluant) to give 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]amino]benzoic acid as a white solid (65%); m.p. (Et2O/hexanes) 125–127° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.35 (br s, 1 H), 9.27 (br s, 1 H), 7.82 (ddd, J=8.3, 6.1, 1.9 Hz, 1 H), 7.08 (dd, J=12.4, 1.7 Hz, 1 H), 7.05–6.96 (m, 2 H), 6.93 (dd, J=8.2, 1.8 Hz, 1 H), 3.33 (t, J=6.4 Hz, 2 H), 3.23 (s, 3 H), 2.59 (t, J=7.7 Hz, 2 H), 1.83–1.73 (m, 2 H). Anal. Calcd for C17H16F3NO3: C, 60.2; H, 4.8; N, 4.1. Found: C, 60.2; H, 4.7; N, 4.1.
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].[CH3:10][C:11]1[C:18]([CH2:19]Br)=[CH:17][CH:16]=[C:15]([NH:21][C:22](=[O:24])[CH3:23])[C:12]=1[C:13]#[N:14]>CO>[C:22]([NH:21][C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[O:5])=[C:11]([CH3:10])[C:12]=1[C:13]#[N:14])(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1ccc(CBr)c(C)c1C#N
Reactant: CC(C)[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(C=O)c(C)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
To a solution of sodium methoxide, 0.43 g, in 100 ml of methanol, was added 0.84 g of 2-nitropropane. After 15 min, 2 g of 2-methyl-3-bromomethyl-6-acetamidobenzonitrile was added and the resulting solution was stirred for 2.5 h at ambient temperature. The solvent was then evaporated at reduced pressure and the residue dissolved in chloroform. The chloroform solution was filtered, washed with H2O, dried and the solvent removed at reduced pressure. The residue was crystallized from chloroform-carbon tetrachloride to yield 0.8 g (53%) of product, m.p. 170°-173° C. NMR (CDCl3) 2.30 (3H, s, CH3CO--N), 2.90 (3H, s, CH3), 8.00 (1H, d, C--5H), 8.6 (1H, d, C--6H), 10.20 (1H, s, (CHO)d. Anal. calc'd for CH11H10N2O2.1/3H2O: C, 63.5; H, 4.84; N, 13.5. Found: C, 63.4; H, 5.00; N, 13.7.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[N:9]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18](Br)=[N:19][CH:20]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:20][N:19]=1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccco1
Product: c1coc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 2-furanylboronic acid (141 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 127 mg, 0.56 mmol, 89%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.12 (s, 2H), 6.52 (dd, J=3.4, 1.5 Hz, 1H), 6.89 (t, J=1.2 Hz, 1H), 7.05 (dd, J=3.4, 0.6 Hz, 1H). 7.09 (brs, 1H), 7.43 (dd, J=8.2, 2.1 Hz, 1H), 7.52 (dd, J=1.5, 0.6 Hz, 1H), 7.56 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 109.2, 112.1, 118.6, 118.9, 129.7, 130.2, 135.6, 137.2, 143.6, 148.4, 149.5, 152.9; MS (ESI): m/z=225.93 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+].[S:35]1[CH2:39][C:38](=[O:40])[NH:37][C:36]1=[O:41]>C1COCC1>[O:41]=[C:36]1[N:37]([CH2:15][C:13]2[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=3)=[O:8])[S:11][CH:12]=2)[C:38](=[O:40])[CH2:39][S:35]1
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Reactant: O=C1CSC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1cccc(F)c1)Nc1nc(CN2C(=O)CSC2=O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Fluoro-benzyl)-3-(4-iodomethyl-thiazol-2-yl)-urea (Intermediate 7, 0.3 mmol) was taken up in THF (3 ml) and DIPEA (1 eq.) and potassium carbonate (1 eq.) was added, followed by thiazolidine-2,4-dione (1 eq.). The reaction was stirred at room temperature overnight. Solvent is removed in vacuo and the crude material was purified by column chromatography with a gradient of 0-60% of (9:1 EtOAc/MeOH) and hexanes to afford 1-(4-((2,4-dioxothiazolidin-3-yl)methyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea (EX #109) as a white solid.