Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.O=[C:28]1[C:36]2[C:31](=[CH:32][C:33]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:34][CH:35]=2)[CH2:30][O:29]1.S(=O)(=O)(O)O>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:28]1[C:36]2[C:31](=[CH:32][C:33]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:34][CH:35]=2)[CH2:30][O:29]1
Reactant: O=C(O)CCc1ccc2c(c1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a stirred solution of 5-fluorooxindole (218 mg, 1.44 mmol) in anhydrous THF (10 ml) under nitrogen was added 1.0M LiHMDS/THF solution (2.9 ml, 2.9 mmol). After the mixture was stirred at room temperature for 10 minutes, 3-(1-Oxo-1,3-dihydro-isobenzofuran-5-yl)-propionic acid (100 mg, 0.48 mmol) was added. After the mixture was stirred at room temperature for 2 hours, 1 M sulfuric acid solution (10 ml) was added. The mixture was heated at 60° C. for 2 hours, and then poured into 150 ml of water. The resulting solid was filtered, rinsed with water, dried in vacuo to give the title compound as a yellow solid (96 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:19]=[N:18][N:17]([C:31](=[O:33])[CH3:32])[CH:16]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1
Reactant: Fc1ccccc1Cn1ncc2cnc(Nc3cn[nH]c3)nc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1cc(Nc2ncc3cnn(Cc4ccccc4F)c3n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-fluorobenzyl)-N-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (56 mg, 0.18 mmol), (Example 88), in DCM (2 mL) were added triethylamine (384, 1.5 eq) and acetyl chloride (154, 1.2 eq). After stirring for 30 min at rt, the reaction mixture was quenched with water. The aqueous phase was extracted with DCM and the combined organic phases dried over sodium sulfate and concentrated in vacuo. The residue was purified with the preparative HPLC to give the title product. 1H NMR (d6-DMSO) δ 10.25 (s, 1H), 9.03 (s, 1H), 8.67 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.41-7.31 (m, 2H), 7.26-7.12 (m, 2H), 5.60 (s, 2H), 2.63 (s, 3H); LC-MS method B, (ES+) 352.0, RT=9.09 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5](C)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC.[C:17](=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (16 g, 61.54 mmol) in DMF (160 mL), iodomethane (35.72 g, 248 mmol) and sodium carbonate (26.28 g, 248 mmol) were added. Resulting reaction mass was stirred at 60° C. for 8 h. On completion, reaction mass was filtered and inorganic solid residue washed with ethyl acetate. Combined filtrates were concentrated under vacuum till dryness. The residue was re-dissolved in ethyl acetate and washed with 5% sodium bicarbonate solution (700 mL) followed by 5M HCl solution (300 mL). Organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford desired compound (16 g, 95%).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Cl[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[N:7]=1.O>C1(C)C(C)=CC=CC=1>[Cl:15][C:8]1[N:7]=[C:6]([O:2][CH3:1])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
Methanol (3.3 g, 103 mmol) in xylene (100 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 2.72 g, 113 mmol) in xylene (300 mL) at 0° C. under an argon atmosphere. After 20 minutes, 2,6-dichloro-3-nitropyridine (20.0 g, 103 mmol) in xylene (300 mL) was added dropwise then the reaction was warmed to ambient temperature and stirred overnight. Water (200 mL) was then added and the two phases were separated. The organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (10:1 hexanes/ethyl acetate) to give the title compound (15.3 g, 78%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:5]=1[NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:5]=1[NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: [H][H]
Reactant: CC(C)C(=O)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)Nc1ccc(C(F)(F)F)cc1N

Procedure:
Shake 85 g. of 2'-nitro-4'-trifluoromethylisobutyranilide in 1.0 liter of ethanol containing 3.0 g. of 5% palladium on charcoal in a parr shaker under approximately 50 lbs. per square inch hydrogen pressure for twenty-four hours. Filter, remove the ethanol and recrystallize from a dichloromethane-chloroform-hexane mixture, obtaining the product of this step.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21]C)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8]C.CC1C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC(C)=CN=1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH3:8]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Agent: Cc1cnc(C)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(3,6-dimethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.32-7.28, 5.58, 4.92, 4.77, 3.28, 3.07, 2.51, 2.38, 2.28; HRMS (FAB) calcd for C15H16BrN3O+H 334.0555, found 334.0557. Anal. Calcd for C15H16BrN3O: C, 53.91; H, 4.83; N, 12.57. Found: C, 53.55; H, 4.88; N, 12.27.
Reaction SMILES: ClC1C=CC(OC)=C(C=1)C(NC[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:22][CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)=O.C1(C(CC)C(O)=O)C=CC=CC=1.C=O.[ClH:41]>>[Cl:41][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:22][CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1
Reactant: CCC(C(=O)O)c1ccc(CCNC(=O)c2cc(Cl)ccc2OC)cc1
Reactant: Cl
Agent: C=O
Agent: CCC(C(=O)O)c1ccccc1
Product: CCC(C(=O)O)c1ccc(CCl)cc1

Procedure:
The 2-[4-(2-aminoethyl)-phenyl]-butyric acid hydrochloride used as starting material is prepared in the following manner: 2-phenylbutyric acid is reacted with paraformaldehyde/hydrochloric acid to give 2-(4-chloromethylphenyl)-butyric acid (b.p. 173°-176° C./0.1 mm Hg). By the reaction thereof with potassium cyanide, there is obtained 2-(4-cyanomethylphenyl)-butyric acid (oil) which, after catalytic hydrogenation, gives 2-[4-(2-aminoethyl)-phenyl]-butyric acid hydrochloride; m.p. 128°-130° C.
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:40][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCNCC2)nc(N2CCOCC2)n1

Procedure:
tert-Butyl 4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate (Example 5) was reacted with TFA in CH2Cl2 to give 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-piperidinyl)-1,3,5-triazin-2-amine, which was reacted directly with methanesulfonyl chloride to give 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine in 83% yield: mp (CH2Cl2/MeOH) 270-272° C.; 1H NMR (DMSO-d6) δ8.11-7.59 (m, 3H), 7.42 and 7.38 (2t, J=8.3. 8.4 Hz, 1H), 6.95 and 6.94 (2m, J=8.0, 7.8 Hz, 1H), 3.98 and 3.97 (2s, 3H), 3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.60-3.56 (m, 2H), 3.56-3.24 (m, 1H), 2.94-2.85 (m, 5H), 2.04-1.97 (m, 2H), 1.65-1.54 (m, 2H); Anal. Calcd. for C22H28F2N8O4S: C, 49.1; H, 5.2; N, 20.8. Found: C, 49.3; H, 5.3; N, 20.9%.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[I:10]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.CN1CCCC1=O>[I:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: Cc1cccc(C)c1N
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1cc(I)cc(C)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 2,6-dimethyl aniline (50 gm) in 1,4-dioxane (400 ml) and N-methylpyrrolidone (40 ml) was added iodine (157.3 gm) slowly at 0° C. The solution was stirred for 1 hour at 0° C. and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 91 gm of 4-iodo-2,6-dimethyl benzenamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([I:17])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][Si:21]([CH2:24][CH2:25][O:26][CH2:27]Cl)([CH3:23])[CH3:22]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][O:26][CH2:25][CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:15]([I:17])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(I)nc2C1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(nc(I)n2COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
To a solution of 2-iodo-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (Preparation 21, 17.25 g, 49.4 mmol) in THF (250 mL) was added NaH (60% in paraffin oil, 2.08 g, 51.9 mmol) and the resulting solution was stirred at room temperature for 1.5 hours. The reaction mixture was cooled to 0° C. and SEM-Cl (9.18 mL, 51.9 mmol) was added dropwise. The reaction was stirred at room temperature for 18 hours, cooled to 0° C. and quenched carefully with water (500 mL). The resulting solution was extracted with EtOAc (2×500 mL) and the combined organics layers were dried over MgSO4, filtered through a pad of silica and concentrated in vacuo to give the title compound (23.4 g) in a 99% yield.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]([CH3:23])([CH3:22])[CH:20]=O.Cl>O.CN(C=O)C>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:18][C:19]([CH3:23])([CH3:22])[CH3:20])[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: CC(C)(C)C=O
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C=C1SC(=S)N(CC(=O)O)C1=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
Into 20 ml of dry DMF was dissolved 1.5 g (0.008 mole) of 3-carboxymethylrhodanine. To the solution was added 2.2 g (0.016 mole) of K2CO3 at a room temperature, and further 1 g (0.012 mole) of 2,2-dimethylpropanal was added dropwise at 60° C. After agitating at 60° C. for 30 minutes, the reaction mixture was poured into water. The resultant was adjusted to pH 4 with a dilute hydrochloric acid and then extracted with ethyl acetate. The extract was purified through a silica gel column and recrystallized from a mixed solvent of ethyl acetate and ethanol to give 1.3 g of 3-carboxymethyl-5-(2,2-dimethylpropylidene)rhodanine in the form of light yellow needle (yield: 63%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][S:14][CH3:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH:20]([CH3:22])[CH3:21].C(Cl)CCl>O1CCOCC1.CN(C1C=CN=CC=1)C>[CH2:19]([O:17][C:16](=[O:18])[C@H:11]([CH2:12][CH2:13][S:14][CH3:15])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CSCC[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: CC(C)CO
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CSCC[C@H](NC(=O)Cc1ccccc1)C(=O)OCC(C)C
Temperature: 23 °C
Reaction time: 17 h

Procedure:
N-Phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolved in 3.0 mL dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol), and catalytic DMAP (0.015 g). After stirring for 17 hours at 23° C., the mixture was evaporated at reduced pressure to an oil, the residue was diluted in EtOAc and washed with 0.1 N HCl and saturated sodium bicarbonate. Chromatography on silica gel using 98:2 CHCl3/MeOH as eluant provided the pure product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@@H:10]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[C:34]([O:38][C:39]([NH:41][C:42]([CH3:47])([C:44](O)=[O:45])[CH3:43])=[O:40])([CH3:37])([CH3:36])[CH3:35].Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl.O>[C:34]([O:38][C:39]([NH:41][C:42]([CH3:47])([CH3:43])[C:44]([NH:11][C@H:10]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Crude D-tryptophan benzyl ester (1.0 g, 3.40 mmol), 1-hydroxybenztriazole hydrate (0.63 g, 4.1 mmol) and t-butoxycarbonyl-α-methylalanine (0.84 g, 4.11 mmol) were stirred together at room temperature in chloroform (20 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg, 5.11 mmol) was added to this mixture in a single portion. The reaction mixture was stirred at room temperature for 4 hours and worked up by pouring into water (50 mL). The chloroform layer was separated and washed with 5% aqueous citric acid solution (25 mL) and 5% aqueous sodium bicarbonate solution (25 mL). The chloroform layer was dried over magnesium sulfate, filtered and evaporated under vacuum to afford a thick oily foam. Chromatography on silica gel using ethyl acetate/hexanes (2:3 v/v) afforded a yellow foam (0.822 g 50%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:18])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]([CH2:2][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[N:21][CH:22]=3)[C:4]=2[F:18])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(CBr)c(F)c1-c1cccc(Cl)c1
Reactant: OB(O)c1ccc(F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 80 °C
Yield: 93.4 %

Procedure:
A flask was charged with 3-Bromomethyl-3′-chloro-2-fluoro-6-methoxy-biphenyl (I-32, 3.3 g, 10 mmol), 2-fluoro-pyridine-5-boronic acid (1.4 g, 10 mmol), toluene (40 mL), 2M aq. Na2CO3 (10 mL, 20 mmol), ethanol (10 mL) and Pd(PPh3)4 (577 mg, 0.5 mmol). The reaction mixture was bubbled with nitrogen gas for 5 minutes. Then the yellow reaction mixture was stirred at 80° C. After overnight stirring the reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was diluted in EtOAc (20 mL) and washed with water (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was purified by silica gel column chromatography, eluted with hexane/EtOAc (9:1) to produce 3.23 g (93% yield) of 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) 3.73 (s, 3H), 3.98 (s, 2H), 6.95 (d, J=8.6 Hz, 1H), 7.11 (dd, J=8.4, 2.8 Hz, 1H), 7.25-7.51 (m, 5H), 7.82 (td, J=8.2, 2.4 Hz, 1H), 8.14 (s, 1H), 8.32 (s, 1H) ppm.
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C([O-])([O-])=O.[Na+].[Na+]>>[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([I:1])=[CH:6][N:5]=1
Reactant: II
Reactant: Oc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1cc(I)cnc1Cl
Reaction time: 8 h

Procedure:
I2 (45.8 g, 0.18 mol) is added to a solution of 2-chloro-3-pyridinol (69, 23.4 g, 0.18 mol) in Na2CO3 (225 ml, 1.0M aqueous solution, 0.225 mol). The I2 initially remains in the bottom of the flask but dissolves with stirring overnight. The solution becomes lighter in color dark and a white solid precipitates. The mixture is then diluted with EtOAc and acidified with concentrated HCl to pH 2–3. The solution is extracted with EtOAc. The combined extracts are washed with H2O, dried, evaporated to give the 2-chloro-5-iodo-3-pyridinol as a yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH3:29])[CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: Cc1ccccc1C(C)O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1C

Procedure:
In a similar manner as described for example B31, 1.50 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 0.63 g of 1-(2-methylphenyl)ethanol, 2.4 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.66 g of di-tert-butyl azodicarboxylate in 40 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:26][CH3:27].[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>CN(C)C=O.C(OCC)(=O)C>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH:21]=[CH:20]5)=[N:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:26][CH3:27])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
A mixture of 7-(3-bromopropoxy)-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (200 mg, 0.47 mmol), (WO 00/47212 A1, Example 314), and 1-acetylpiperazine (180 mg, 1.40 mmol) in N,N-dimethylformamide (4 ml) was stirred at ambient temperature for 3 hours. The mixture was diluted with ethyl acetate and washed with brine (×2), dried (MgSO4) and concentrated under reduced pressure. Column chromatography of the residue (5% methanol/dichloromethane) gave 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (109 mg, 49%) as a white solid.
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.ClCCCC(OC(=O)C)CCCCC(F)(F)F.C([O:35][CH:36]([CH2:56][CH2:57][CH2:58][CH2:59][C:60](F)(F)F)[CH2:37][CH2:38][CH2:39][N:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53]CC)=[O:52])[S:41]([CH3:44])(=[O:43])=[O:42])(=O)C>>[OH:35][C@H:36]([CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:37]#[C:38][CH2:39][N:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=[O:52])[S:41]([CH3:44])(=[O:42])=[O:43]
Reactant: CCOC(=O)CCCCCCN(CCCC(CCCCC(F)(F)F)OC(C)=O)S(C)(=O)=O
Agent: CC(=O)OC(CCCCl)CCCCC(F)(F)F
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1, except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-9,9,9-trifluorononane (Example E). The product of Step A is thus ethyl 7-[N-(4-acetoxy-9,9,9-trifluorononyl)methanesulfonamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxy-9,9,9-trifluorononyl)methanesulfonamido]heptanoic acid (B).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]([NH:28]C(=O)OC(C)(C)C)([CH3:27])[CH3:26])=[CH:19][CH:18]=1)[CH3:9]>ClCCl>[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]([CH3:27])([CH3:26])[NH2:28])=[CH:19][CH:18]=1)[CH3:9]
Reactant: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl [2-({6-[(2-ethylphenyl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 77, 88.6 mg) was dissolved in dichloromethane (2 mL) to give a yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 minutes, the solvent was evaporated under vacuum affording a yellow oil that was charged on a 5 g SCX cartridge and was then flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (67.1 mg).