Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@H:5]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH2:9][CH3:10])[C:7](=[O:26])[CH2:6]1)[C@@H:20]1[C:15]([CH:16]=[C:17]([O:24][CH3:25])[CH2:18][CH2:19]1)=[CH:14][CH2:13]3)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:25][O:24][C:17]1[CH2:18][CH2:19][C@H:20]2[C:15](=[CH:14][CH2:13][C@@H:12]3[C@@H:21]2[CH2:22][CH2:23][C@@:8]2([CH2:9][CH3:10])[C@H:11]3[CH:5]=[CH:6][C:7]2=[O:26])[CH:16]=1
Reactant: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 50 °C
Yield: 80.2 %

Procedure:
A mixture of 15α-acetoxy-3-methoxy-18-methyl-estra-3,5-dien-17-one (1 g, 2.8 mmol) in suspension in a 1/1 MeOH/water solution (20 ml), and potassium carbonate (1 g, 7.23 mmol) was heated at 50° C. for 1 h. The mixture was allowed to cool to room temperature and the precipitate was filtered, washed with water and dried under vacuum to afford 3-methoxy-18-methyl-estra-3,5,15-trien-17-one (0.67 g, yield: 80%). mp: 159-161° C.; 1H-NMR δ=0.72 (t, 3H), 0.9-2.4 (m, 16H), 3.55 (s, 3H), 5.18 (s, 1H), 5.28 (d, 1H), 5.95 (m, 1H), 7.45 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([Sn](CCCC)(CCCC)CCCC)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:22]1[N:26]([S:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:25]=[C:24]([CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1>C1(C)C=CC=CC=1.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>[CH3:45][N:37]([CH2:36][C:24]1[CH:23]=[C:22]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:26]([S:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:25]=1)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:41])[CH3:42]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccnc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 25 °C
Yield: 22.3 %

Procedure:
A solution of 3-methyl-2-(tributylstannyl)pyridine (1.0 g), tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (563 mg) and tetrakis(triphenylphosphine)palladium (454 mg) in toluene was stirred under a nitrogen atmosphere at 120° C. for 30 hr. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless oil (yield 129 mg, 22%).
Reaction SMILES: C(O)(=O)CC.C(O)(=O)C1C=CC=CC=1.O.[C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH:17](C)[CH3:18]>>[C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH2:17][CH3:18]
Reactant: CC(C)C(=O)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: CCC(=O)O
Product: CCC(=O)c1ccccc1
Reaction time: 4.5 h
Yield: 2360.1 %

Procedure:
In Example 1, using the reactor described above, together with ancillary equipment, a mixture containing 2 moles of propionic acid per mole of benzoic acid was fed to the reactor together with 4 moles of water per mole of benzoic acid at a rate of 249 ml/hr. for 4.5 hours. The reaction temperature was maintained between 445° C. and 450° C. Analysis of the condensed organic layer by gas chromatography indicated that 4.68 pounds of isobutyrophenone were produced per 100 pounds of propiophenone. These data are delineated in Table I. The instrument used was a Bendix Model 2300 dual column programmed temperature gas chromatograph having a thermal conductivity detector. The bridge current was 200 ma. with a 0-1 mv. recorder. The column consisted of two, 10 feet by 1/8 inch stainless steel tubing packed with silicone on an inert support. The column temperature was 190° C. The carrier gas was helium at 30 cc/minute.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:19])=[CH:5][CH:4]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:28][CH2:27][N:29]([CH2:33][CH3:34])[CH2:30][CH3:31])=[CH:24][CH:25]=2)=[O:19])=[CH:5][CH:4]=1
Reactant: CCN(CC)CCCl
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3ccccc23)cc1

Procedure:
By essentially following the procedure outlined in Example 3, part D, the title compound was prepared from 4-hydroxyphenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone (Example 28, Part A) and 2-diethylaminoethyl chloride in 86% yield. Flash chromatography [SiO2; gradient 1-4% of (1:1 TEA-MeOH) in EtOAc] gave the desired compound as a light oil.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[N:26]=1>O1CCCC1>[CH3:23][O:22][C:20]([C:15]1[C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][NH:6][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([C:35]([F:37])([F:38])[F:36])[N:26]=3)=[CH:9][CH:10]=2)=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21]
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: FC(F)(F)c1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(CNc2nc(C(F)(F)F)nc3ccccc23)cc1
Reaction time: 72 h
Yield: 110.8 %

Procedure:
Sodium acetate (2.34 g), 4'-aminomethyl(1,1'-biphenyl)-2-carboxylic acid, methyl ester (1.99 g) and 1.66 g of 4-chloro-2-trifluoromethylquinazoline were added to 50 mL of tetrahydrofuran. The resulting suspension was stirred at 40°-50° C. for 72 hours. All the THF was removed by evaporation and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel chromatography to yield. 3.46 g (40%) of the desired product (M.P.=135°-142° C.): 1H NMR (DMSO-d6, 400 MHz) δ 9.43 (t, J=6 Hz, 1H), 8.41 (d, 7.9 Hz, 1H), 7.88 (m, 2H), 7.70 (m, 2H), 7.58 (m, 1H), 7.43 (m, 4H), 7.25 (m, 2H), 4.85 (d, J=5.9 Hz, 2 H), 3.56 (s, 3H); positive FAB MS m/e 438 (MH). Anal Calcd for C24H18F3N3O2.0.5H2O: C, 64.57; H, 4.29; N, 9.41. Found: C, 64.83; H, 4.02; N, 9.48.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+].[ClH:37]>O.CN(C)C=O>[ClH:37].[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCBr
Reactant: c1ccc2c(c1)CCc1ccccc1C2=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 3.00 g of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 2.34 g of ethyl 4-bromobutyrate, 1.51 g of potassium carbonate and 18 ml of N,N-dimethylformamide was stirred at 70° C. for 3 hrs. After cooling, water was added to the reaction mixture and then extracted with ether. The ether layer was washed with water, dried and concentrated to give pale brown solid, which was converted to the hydrochloride in the usual manner to give 3.88 g of colorless solid. The crude hydrochloride was recrystallized from a mixture of acetone and ether to give colorless crystals, mp 182°-184° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].OS(O)(=O)=O.[F:18][CH:19]([F:31])[C:20](=O)[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.C(O)(C)C.FC(F)C(=O)CC(C1C=CC=CC=1)=O>C(O)(C)C.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][C:20]([CH:19]([F:18])[F:31])=[N:12]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C(CC(=O)C(F)F)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2ccccc2)nc1
Temperature: 24 °C
Reaction time: 1 h

Procedure:
To a clean and dry nitrogen purged 22 L round bottom flask under nitrogen atmosphere was charged: 500 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (2.67 moles), 10 L water (20 volumes) and 579 mL of concentrated H2SO4 (0.063 volumes). In a separate 12 L 3-neck round-bottomed flask was prepared a solution of 7500 mL of isopropanol (15 volumes) and 508 g (2.56 moles) of 4,4-difluoro-1-phenyl-1,3-butanedione. The isopropanol/4,4-difluoro-1-phenyl-1,3-butanedione solution was added to the mixture containing the 5-(methylsulfonyl)-2-hydrazinyl-pyridine, keeping the pot temperature below 30° C. After addition of the 4,4-difluoro-1-phenyl-1,3-butanedione solution, the mixture was stirred at 24° C. for 1.0 hour and sampled for disappearance of 5-(methylsulfonyl)-2-hydrazinyl-pyridine by HPLC. The pot was then heated to 40° C. for 2 hours until disappearance of the intermediate compound of formula 4 and the resulting slurry was filtered and washed with water to achieve a pH of the filtrate of from about 6-7. The solids were then charged to a 5L 3-neck round-bottom flask. To the flask was added 1250 mL water (2.5 volumes) and 1250 mL isopropanol (2.5 volumes). The mixture was heated to reflux (85° C.) for 2 hours. The pot was then cooled to 40° C. and then stirred overnight. The solids were isolated by filtration, washed with 2 L isopropanol, and dried in a vacuum oven at 45° C. The compound of formula 6 was present at a level of 1.2% by HPLC (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45.
Reaction SMILES: [F:1][C:2]1([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:4][CH:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:20]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[F:1][C:2]1([C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:20])=[O:16])=[CH:13][CH:12]=2)[CH2:4][CH:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(C2(F)CC2c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C2(F)CC2c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.35 g of 4-(1-fluoro 2-phenyl cyclopropyl) benzoic acid (mixture (B)), obtained according to Preparation 1, and 20 cm3 of dichloromethane are mixed together under an inert gas atmosphere, the mixture is cooled down to 0° C., 0.207 g of commercial oxalyl chloride and 0.01 cm3 of dimethylformamide are added, the whole is agitated for 3 hours at 20-250° C. and brought to dryness in order to collect the acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[CH3:14])=[O:4].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[CH2:14][Br:15])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(C)c1CBr
Yield: 51.5 %

Procedure:
A mixture of 5-bromo-1,2-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (540 mg, 2.08 mmol), N-bromosuccinimide (388 mg, 2.18 mmol), and benzoyl peroxide (50 mg, 0.208 mmol) in CCl4 (20 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-50% EtOAc/hexanes) to give 363 mg of the title compound. MS: (+) m/z 340.02 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:16][C:9]2[N:10]=[C:11]([NH2:15])[N:12]=[C:13](Cl)[C:8]=2[CH:7]=1)=[O:5])[CH3:2].[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][C:27]#[N:28])=[CH:25][C:20]=2[O:19][CH2:18]1.[H-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[S:16][C:9]2[N:10]=[C:11]([NH2:15])[N:12]=[C:13]([CH:26]([C:24]3[CH:23]=[CH:22][C:21]4[O:17][CH2:18][O:19][C:20]=4[CH:25]=3)[C:27]#[N:28])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: N#CCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1cc2c(Cl)nc(N)nc2s1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(C(C#N)c3ccc4c(c3)OCO4)nc(N)nc2s1
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (1 equiv.) and benzo[1,3]dioxol-5-yl-acetonitrile (1 mole eq.) in DMF at room temperature, sodium hydride (1.1 mole eq., 60% in mineral oil) was added. The mixture was stirred at this temperature overnight under argon. After that, it was diluted with brine and extracted with ethyl acetate. The combined organic portions were washed with brine and water and dried with sodium sulphate. After filtration and evaporation of the solvent, brown solids were obtained which were purified either by preparative TLC or preparative HPLC.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[Cl:8][C:9]1[CH:14]=CC(O)=[CH:11][CH:10]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[C:5]([O:4][C:1]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 97.7 %

Procedure:
Acetic anhydride (80.1 g, 0.78 mol) and one drop of concentrated sulfuric acid were added to 4-chlorophenol [compound (6-1)] (100 g, 0.78 mol) at room temperature, and the mixture was stirred for 17 hours. The resultant mixture was added to ice-water, and converted to alkaline by the addition of sodium hydroxide (20% aqueous solution), followed by extraction with diethyl ether. The organic layer was washed with water, dried over magnesium sulfate. Subsequently, the solvent was removed under reduced pressure, and then the residue was subjected to distillation under reduced pressure (81° C./1.5 mmHg), to thereby yield 4-chlorophenyl acetate as a colorless oily product (130 g, yield: 98.0%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([OH:16])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:16][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]([CH2:12][C:13]([NH2:15])=[O:14])=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CBr
Reactant: CCc1c(CC(N)=O)c2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(CC(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (135 mg, 0.44 mmol) was added to 17.6 mg (0.44 mmol) of NaH/mineral oil (washed with hexanes) in 5 mL of DMF, stirred 0.5 hour, 0.04 mL (0.44 mmol) of methyl 2-bromoacetate added and stirring maintained for 5 hours. The mixture was diluted with water, extracted with ethyl acetate. Some material was insoluble and was filtered. The ethyl acetate was washed with brine, dried (MgSO4) and concentrated. The residue was combined with the filtered material to give 119 mg (71% yield) of 2-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.[NH:25]1[CH2:27][CH2:26]1.O>O1CCCC1>[N:25]1([C:22]([C:9]2[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]3[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=3[CH:8]=2)=[O:24])[CH2:27][CH2:26]1
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Reactant: C1CN1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c3c(c(C(=O)N4CC4)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.9 %

Procedure:
To a suspension of 260 mg (0.81 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]-imidazole-5-carboxylic acid in tetrahydrofuran (10 ml) were added 157 mg (1.0 mmol) N,N′-carbonyl-diimidazole (CDI) and the reaction was stirred at room temperature overnight 105 mg (2.4 mmol) Aziridine were added and the mixture was stirred for 16 h at room temperature. The reaction was poured into water and extracted with dichloromethane. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=20:1) and crystallized from n-butanol to afford 56 mg (20%) of the title compound as a white solid. m.p. 201°-204° C.
Reaction SMILES: [CH3:1][O:2][Si:3]([O:20][CH3:21])([O:18][CH3:19])[CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][CH2:10][Si:11]([O:16][CH3:17])([O:14][CH3:15])[O:12][CH3:13].[CH:22]([N:25]=[C:26]=[N:27][CH:28]([CH3:30])[CH3:29])([CH3:24])[CH3:23]>>[CH3:15][O:14][Si:11]([O:16][CH3:17])([O:12][CH3:13])[CH2:10][CH2:9][CH2:8][N:7]([CH2:6][CH2:5][CH2:4][Si:3]([O:20][CH3:21])([O:18][CH3:19])[O:2][CH3:1])[C:26]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:25][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)N=C=NC(C)C
Reactant: CO[Si](CCCNCCC[Si](OC)(OC)OC)(OC)OC
Product: CO[Si](CCCN(CCC[Si](OC)(OC)OC)C(=NC(C)C)NC(C)C)(OC)OC
Reaction time: 2 h

Procedure:
A mixture of 30.84 g of bis(3-(trimethoxysilyl)propyl)amine (0.0903 mol) and of 13.68 g of diisopropylcarbodiimide (0.1084 mol, 20% excess) was heated for 31 h at 110° C. (amine conversion of 94%). The final colorless mixture was devolatilized at 100° C. under 2 mbar for 2 h to give 42 g of a colorless, low-viscosity liquid corresponding to the expected guanidine, containing 4% of the initial amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[C:36]2[CH:35]=[C:34]3[O:37][CH2:38][O:39][C:33]3=[CH:32][C:31]=2[N:30]=[CH:29][N:28]=1>CN(C=O)C.CCOC(C)=O>[O:37]1[C:34]2=[CH:35][C:36]3[C:27]([O:23][C:20]4[CH:21]=[CH:22][C:17]([C:12]5[C:13](=[O:16])[N:14]([CH3:15])[C:9]([NH:8][C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[N:10][CH:11]=5)=[N:18][CH:19]=4)=[N:28][CH:29]=[N:30][C:31]=3[CH:32]=[C:33]2[O:39][CH2:38]1
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)cn2)c1=O
Reactant: Clc1ncnc2cc3c(cc12)OCO3
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(Oc3ncnc4cc5c(cc34)OCO5)cn2)c1=O
Temperature: 25 °C
Yield: 113.4 %

Procedure:
2-(4-Fluoro-phenylamino)-5-(5-hydroxy-pyridin-2-yl)-3-methyl-3H-pyrimidin-4-one (2.18 g, 7 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 8-Chloro-[1,3]dioxolo[4,5-g]quinazoline (2.08 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude title compound and further purification to yield product (3.68 g, 90%). 1HNMR (400 MHz, DMSO): 9.18 (s, 1H), 8.60 (m, 3H), 8.45 (d, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.55 (m, 3H), 7.21 (m, 2H), 4.15 (s, 2H). LC/MS Calcd for (M+H)+485.4. found 485.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:33])[CH3:32])=[CH:3][CH:4]=2)=[CH:9][C:10]=1[O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (100 mg, 0.28 mmol) in acetonitrite (3 mL) at 0° C., was added pyridine (0.035 mL, 1.5 eq.) and acetic anhydride (0.03 mL, 0.28 mmol). The mixture was stirred at room temperature over night, and the precipitate was filtered to provide N-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl) acetamide as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@@H:49]([CH2:63][C:64]1[CH:69]=[C:68]([F:70])[CH:67]=[C:66]([F:71])[CH:65]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1>C(Cl)Cl>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:48][C@@H:49]([CH2:63][C:64]3[CH:65]=[C:66]([F:71])[CH:67]=[C:68]([F:70])[CH:69]=3)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=3)=[O:16])[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c[nH]c2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1c[nH]c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.4 %

Procedure:
To a mixture of 3-Butyl-1H-indole-5-carboxylic acid (0.145 g) in methylene chloride (15 mL) was added triethylamine (0.068 g), and HATU (0.255 g). The mixture was stirred at room temperature for 15 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.224 g) was added. The mixture was stirred at room temperature for 72 h then poured into methylene chloride (50 mL), washed with water then saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under vacuum. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride with 0.15% HOAc as eluent to give 0.247 g of the title compound: MS (ESI+) for C32H37F2N3O2 m/z 534.3 (M+H)+.