Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:20]([CH2:19][CH3:18])[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)C(C)(C)CCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)C(CC)Oc1ccc(C(C)=O)cc1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A mixture of 30 g of p-hydroxyacetophenone and 30 g of potassium carbonate was stirred in 500 ml of ethanol at 60° C. for 30 minutes. After cooling to room temperature, 52 g of ethyl 5-bromo-2,2-dimethylpentanoate was added to the reaction mixture. The resulting mixture was heated under reflux overnight while stirring. The solvent was removed from the reaction mixture by distillation and, 500 ml of chloroform and 300 ml of a 5% aqueous hydrogen sodium carbonate solution were added to the residue. After stirring the mixture, the chloroform layer was fractionated and washed successively with water and then with a saturated aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. Removal of chloroform by distillation gave a residual oily substance. The oily substance was subjected to silica gel column chromatography and eluted using chloroform as an eluant to give 42 g of ethyl p-acetylphenoxy-2,2-dimethylpentanoate as an oily substance. The thus obtained oily substance was dissolved in 1.6 l. of anhydrous methylene chloride and 24 g of bromine was dropwise added to the solution under ice cooling while stirring to allow to react for 3 hours. To the reaction mixture was added 1 liter of ice water. After thoroughly stirring, the organic layer was successively washed with water and with a saturated aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. Removal of methylene chloride by distillation gave the aimed product, ethyl 5-[p-(bromoacetyl)phenoxy]-2,2-dimethylpentanoate, as an oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13]1>COCCOC>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13]2)=[N:3][CH:4]=1
Reactant: Clc1ncnc2ccccc12
Reactant: CCOC(=O)CC1CNc2ccccc21
Solvent: COCCOC
Product: CCOC(=O)CC1CN(c2ncnc3ccccc23)c2ccccc21

Procedure:
A mixture of 4-chloroquinazoline (2.3g.) and ethyl indolin-3-ylacetate (2.6g.) in 1,2-dimethoxyethane (30ml.) was heated under reflux for 15 minutes. The mixture was cooled and filtered, and the solid residue was dissolved in ice-water (40ml.). To the solution was added saturated sodium acetate solution (10ml.), and the mixture was extracted with ethyl acetate (3 × 50ml.). The combined extracts were dried (Na2SO4), and the solvent evaporated in vacuo to give ethyl 1-quinazolin-4-ylindolin-3-ylacetate as a syrup which was proved to be pure by TLC (system A).
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][C@H:4]1[C@@H:6]([C:7]([O-:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[Cl:13]/[CH:14]=[CH:15]\[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]([Br:12])=[CH:3][C@H:4]1[C@@H:6]([C:7]([O:9][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([CH2:16]/[CH:15]=[CH:14]\[Cl:13])=[CH:18][CH:19]=2)=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: OCc1ccc(C/C=C\Cl)cc1
Reactant: CC1(C)[C@H](C(=O)[O-])[C@@H]1C=C(Br)Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)OCc2ccc(C/C=C\Cl)cc2)[C@@H]1C=C(Br)Br
Reaction time: 0.5 h

Procedure:
To a solution of (1R)cis 3(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylate (0.11 g) in CH2Cl2 (3 ml) cooled to 0° is added successively 4(Z-3-chloroallyl)benzyl alcohol (0.070 g) in CH2Cl2 (2 ml), N,N1 dicyclohexylcarbodiimide (0.076 g) in CH2Cl2 (2 ml), and 4-dimethylamino pyridine (0.010 g). This mixture is stirred for 30 minutes at 0°, then for 16 hours at 20°. The resulting precipitate is filtered off, the filtrate evaporated under reduced pressure and the residue chromatographed on florisil. The fraction eluted by 7% diethyl ether in petroleum ether bp 60°-80° C. ether in petrol is evaporated to a residue of 4(-3-chloroallyl)benzyl (1R)cis-3(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylate (0.15 g) 91% nD20 1.5684.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:9]1[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:37])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35]C)=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O.CO.[OH-].[Na+]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:9]1[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:37])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([OH:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3OC)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1[C@H]1SC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 33.8 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 77, but starting from 0.76 g of methyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-methoxyphenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenylacetate in 6 cm3 of a water/methanol (30/70 by volume) mixture and 0.09 g of potassium hydroxide. The crude product (0.45 g) is dissolved in 7.5 cm3 of a 0.1N aqueous sodium hydroxide solution. The solution thus obtained is washed with 2 times 10 cm3 of diethyl ether, brought to a pH of 2 by addition of a 1N aqueous sulphuric acid solution, then extracted with 2 times 20 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in diisopropyl ether, 0.25 g of (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-methoxyphenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenylacetic acid is thus obtained in the form of an amorphous product ([α]D20 =+6.4°±1.0° (C=0.466%; CHCl3), [proton NMR (200 MHz, DMSO D6 plus several drops of CD3COOD, δ in ppm, J in Hz), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 1.55 (s, 9H, --C(CH3)3); 3.22 and 3.45 (2dd, J=12.5 and 7, 2H, S--CH2 --); 3.51 (s, 2H, ArCH2COO--); 3.65 (bd, 1H of N--COCH2 --N); 3.93 (s, 3H, --OCH3); 4.05 (d, J=17.5, 1H, the other H of N--COCH2 --N); 4.91 (t, J=7, 1H, N--CH--COO); 6.5 (s, 1H, S--CH--N); 6.85 (bd, J=8, 1H, in position 4 on CO--NM--Ph); 6.9 to 7.4 (m, 6H, aromatic); 7.9 (bd, J=8, 1H, in position 6 on S--CH--Ph--)], [infrared spectrum (KBr), characteristic bands in cm-1 : 3390, 2975, 2930, 2840, 2700 to 2250 (broad band), 1735, 1645, 1610, 1600, 1595, 1560, 1495, 1370, 1245, 1155, 1025, 760, 705].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:39])([F:38])[CH2:19][N:20]1[C:24]([CH2:25]O)=[CH:23][C:22]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[N:21]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:25][C:24]3[N:20]([CH2:19][C:18]([F:38])([F:17])[F:39])[N:21]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=4)[CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: OCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:23][N:24]=3)[CH:18]=2)[N:13]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:12]=1.Cl.[CH3:40][NH2:41].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:41][CH3:40])=[O:7])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:27])[CH3:28])=[N:23][N:24]=3)[CH:18]=2)[N:13]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(C(=O)O)ccc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CN
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CNC(=O)c1ccc(F)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of 4-fluoro-3-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)benzoic acid (500 mg, 0.936 mmol) and methylamine hydrochloride (97 mg, 1.40 mmol) in pyridine (10 mL) was added POCl3 (0.13 mL, 1.40 mmol). The reaction was stirred at RT for 1 h, then quenched with ice cold water (20 mL) to get a precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried. The crude product was purified with basic alumina chromatography (eluting with EtOAc) to give 4-fluoro-3-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)-N-methylbenzamide (250 mg, 48%). MS (ESI, pos. ion) m/z: 548.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([C:22]([O:24]CC)=[O:23])[C:3]=1[F:27].C(O)C.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([C:22]([OH:24])=[O:23])[C:3]=1[F:27]
Reactant: CCOC(=O)c1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(C(=O)O)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 90.1 %

Procedure:
121 mg (0.320 mmol) of Compound 92 obtained in Example 92 (2) was suspended in a mixed solvent of 10 mL of ethanol and 5 mL of methanol, 0.4 mL of a 5N aqueous solution of sodium hydroxide was added and the mixture was stirred at 50° C. for 2.5 hours. The reaction solution was cooled on ice, the solution was adjusted to pH 4 and the precipitated crystals were collected by filtration to give 101 mg of Compound 93 (yield: 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([CH2:21][CH3:22])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:26][CH2:27][C:28]1[C:33]([N:34]2[CH2:45][CH2:44][N:43]3[C:36](=[CH:37][C:38]4[CH2:39][C:40]([CH3:47])([CH3:46])[CH2:41][C:42]=43)[C:35]2=[O:48])=[CH:32][C:31]([F:49])=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1)(=O)C>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[CH2:21]([N:16]1[CH2:15][CH2:14][C:13]2[N:12]=[C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([C:29]4[C:28]([CH2:27][OH:26])=[C:33]([N:34]5[CH2:45][CH2:44][N:43]6[C:36](=[CH:37][C:38]7[CH2:39][C:40]([CH3:46])([CH3:47])[CH2:41][C:42]=76)[C:35]5=[O:48])[CH:32]=[C:31]([F:49])[CH:30]=4)[CH:3]=3)[CH:20]=[CH:19][C:18]=2[CH2:17]1)[CH3:22]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CCN1CCc2nc(Nc3cc(Br)cn(C)c3=O)ccc2C1
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: COCCOC
Product: CCN1CCc2nc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4CO)cn(C)c3=O)ccc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
In a 48-mL sealed tube equipped with a magnetic stirring bar were placed 5-bromo-1-methyl-3-(6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one (143 mg, 0.4 mmol), 10-[2-(acetoxymethyl)-3-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]-dodeca-2(6),7-dien-9-one 230a (496 mg, 1.0 mmol), Pd(PPh3)4 (23 mg, 0.020 mmol) in 2 N Na2CO3 (4 mL) and DME (4 mL). After the reaction mixture was stirred at 100° C. for 1 h, it was purified by flash chromatography (dichloromethane:methanol, 3:1) to give 7% (18 mg) of 284 MS (ESI+) m/z 611.5 (M+H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[OH-].[Na+].[C:11]([O:15][C:16](OC([O-])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1>[C:11]([O:15][C:16]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.8 %

Procedure:
To a solution of 108 g of o-phenylenediamine (1.0 mol) in 1000 mL of dioxane was added. 500 mL of 1N sodium hydroxide aq., and then 218 g of tert-butyldicarbonate (1.1 mol) in 500 mL of dioxane under ice-cooling. After stirring for 6 hours at room temperature, the mixture was left overnight. The mixture was concentrated to ½ volume by evaporation, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography (eluent: chloroform) to give a solid, which was then washed with diethyl ether to give 68.4 g of N-tertbutoxycarbonyl-o-phenylenediamine (Yield: 32.8%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: Nc1ccc(I)cc1F
Reactant: Cc1c(Cl)c(C(=O)O)nn(C)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)nn(C)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.6 %

Procedure:
To a suspension or 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (200 mg, 0.99 mmol) and 2-fluoro-4-iodoaniline (478 mg, 1.97 mmol) in THF (6.5 mL) at −78° C. was slowly added a solution of LiHMDS (3.00 mL, 3.00 mmol, 1 M solution in THF). After complete addition, the resulting mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with 6 N aqueous HCl (8 mL) at 0° C., warmed to room temperature, and stirred for 1.5 hours. The precipitates were filtered, washed with water and ether, and triturated with ether to afford 158 mg (38%) of the desired product.
Reaction SMILES: C1(C[CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27](C4C=CC=CC=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])CCCCC1.N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)C[CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[CH:15]1([CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:54]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])[CH2:45][CH2:44][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: O=C(NC(C(=O)O)C1CCCCC1)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 48 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Cha Wang resin (250 mg, 0.4 mmol/g), producing 29 mg of the title compound (48% yield). MS: 586.27 (M−H+) HPLC Procedure A, retention time=14.94 min.
Reaction SMILES: Br[CH:2]([C:16](=O)[CH3:17])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][C:16]1[NH:27][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:26][C:2]=1[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: N=C(N)c1ccccc1
Reactant: CC(=O)C(Br)CCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2)nc1CCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 41.5 %

Procedure:
To a solution of 2-(3-bromo-4-oxo-pentyl)-isoindole-1,3-dione (12.4 g) [CAS 112357-34-3] in abs. DMF (50 ml) was added benzamidine 85% (5.65 g) and potassium carbonate (11.03 g). The reaction mixture was stirred at 80° C. for 4 h, concentrated under vacuum. To the residue was added ice/water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate and concentrated. The crude product was purified by chromatography on silica gel using methylene chloride/methanol 5% and 10% as eluent to obtain 2-[2-(5-methyl-2-phenyl-1H -imidazol-4-yl)-ethyl]-isoindole-1,3-dione (5.5 g) as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.O=[C:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH:12]1[C:11]2[NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=3[C:15]=2[CH2:14][CH2:13]1)[CH3:21]
Reactant: Nc1ccc(F)cc1I
Reactant: CCOC(=O)CC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(F)cc21
Temperature: 115 °C
Yield: 53.1 %

Procedure:
A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2-oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115° C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene to provide 5.36 g of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[C:11](=O)[CH:10]([CH3:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:25]([N:32]1[C:11]2[CH:10]([CH3:24])[CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][C:12]=2[CH:14]=[C:15]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: CC1CN(Cc2ccccc2)CC(CC(=O)c2ccccc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1CN(Cc2ccccc2)Cc2cc(-c3ccccc3)n(Cc3ccccc3)c21
Yield: 84.4 %

Procedure:
A mixture of 1-benzyl-3-methyl-5-phenacyl-4-piperidone (3.2 g), benzylamine(1.1 g), p-toluenesulphonic acid (0.1 g) and dry toluene (100 ml) was heated under reflux under a Dean and Stark trap for 3 days. Removal of thesolvent left a yellow solid, which on recrystallisation from methanol gave 3.3 g of the product as pale yellow prisms. M.pt. 131° C (Found: C 85.2; H, 7.2; N, 7.1. C28H28N2 requires: C, 85.7; H, 7.2;N, 7.1%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)=[CH:5][CH:4]=1.Br[C:21]1[CH:29]=[C:28]2[C:24]([C:25]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][C:26]=3[N:27]2[CH3:30])=[CH:23][CH:22]=1>>[CH3:30][N:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=4)=[CH:12][C:13]3=[O:17])[CH:29]=2)[C:25]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][C:26]1=2
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 21.4 %

Procedure:
4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (100 mg, 0.37 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (135 mg, 0.370 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (44 mg, 21%) as a yellow/brown solid: 1H NMR (300 MHz, CDCl3) δ 8.81 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.37-7.34 (m, 1H), 7.27 (1H, under solvent peak), 7.02 (dd, J=8.3, 1.7 Hz, 1H), 6.07-6.04 (m, 2H), 5.16 (s, 2H), 4.64 (br m, 2H), 3.75 (br m, 2H), 3.63 (s, 3H), 2.80 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(Oc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 43 %

Procedure:
A solution of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.200 g, 0.79 mmol), methyl 2-(4-hydroxyphenyl)acetate (0.131 g, 0.79 mmol) and potassium carbonate (0.546 g, 3.95 mmol) in acetonitrile (5 mL) was heated to 85° C. for 7 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (0.130 g, 65%). MW=382.84. 1H NMR (CD3OD, 500 MHz) δ 8.21 (t, J=1.8 Hz, 1H), 8.16-8.12 (m, 1H), 7.46-7.35 (m, 4H), 7.21-7.17 (m, 2H), 6.77 (s, 1H), 3.73 (s, 2H), 3.72 (s, 3H), 2.83 (q, J=7.6 Hz, 2H), 1.35 (t, J=6.4 Hz, 3H); APCI MS m/z 383 [M+H]+.