Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][CH3:19])=[C:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC4C=CC=CC=4)=[CH:22][CH:21]=1)[C:12]3=[C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[CH:35]=2)C1C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH2:18]([C:14]1[C:15]2[N:11]3[C:10](=[CH:35][C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:12]3[C:13]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:9]([OH:8])=[CH:17][CH:16]=2)[CH3:19]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCCCCN3CCCCC3)cc3c(OCc4ccccc4)ccc1n32
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1c(-c2ccc(O)cc2)c2c(COCCCCCCCCN3CCCCC3)cc3c(O)ccc1n32
Yield: 85.4 %

Procedure:
A suspension of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-((8-piperidinooctyloxy)-methyl)pyrrolo[2,1,5-cd ]indolizine (0.30 g, 0.44 mmol) and 30 mg 10% palladium on charcoal in 12 ml of ethanol and 8 ml of tetrahydrofuran was stirred in a hydrogen atmosphere for 6 hours. The reaction mixture was filtered twice and the solvent was evaporated. The resulting oil was purified by column chromatography over netural aluminium oxide activity grade I, using 10% of methanol in dichloromethane as the eluent. The product was crystallised from dichloromethane, diethyl ether and petroleum ether to afford 189 mg (85%) of 1-ethyl-5-hydroxy-2-(4-hydroxyphenyl)-3-((8-piperidinooctyloxy)methyl)pyrrolo[2,1,5-cd ]indolizine as yellow crystals. M.p. 91-95° C. (decomp.). MS(FAB): m/z 503 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ:1.17-1.71 (m, 21H); 2.61-3.09 (m, 8H); 3.38 (t, 2H); 4.68 (s, 2H); 6.92 (d, 2H); 7.12 (d, 1H); 7.22 (s, 1H); 7.48 (d, 2H); 7.83 (d, 1H); 9.58 (s, 1H); 10.59 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.5 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (45 mg, 35%).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:42])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:42])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][CH:31]=1
Reactant: CC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)cc1
Yield: 28.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (800 mg, 4.84 mmol) was reacted with tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (1.5 g, 4.16 mmol) to afford the desired product (550 mg, 46%) as a brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([C:17]3([O:27][CH3:28])[CH2:21][CH2:20][N:19]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:18]3)[CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:30][OH:31]>>[OH:31][N:30]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([C:17]3([O:27][CH3:28])[CH2:21][CH2:20][N:19]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:18]3)[CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: NO
Reactant: COC1(c2cccc(Sc3ccc(C(C)=O)cc3)c2)CCN(CC(F)(F)F)C1
Agent: Cl
Product: COC1(c2cccc(Sc3ccc(C(C)=NO)cc3)c2)CCN(CC(F)(F)F)C1
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 27, 3-[3-(4-acetylphenylthio)phenyl]-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine was reacted with hydroxylamine hydrochloride to give 3-{3-[4-(1-hydroxyiminoethyl)phenylthio]phenyl}-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine in 63% yield, m.p. 86°-88° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:17])[CH2:6][CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2>CO>[CH:14]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]([CH2:9]3)[CH:7]1[CH2:6][C:5]([OH:17])=[O:4])[CH2:13]2
Reactant: COC(=O)CC1C2CC3CC(C2)CC1C3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Aqueous 2.5 N sodium hydroxide solution 433 ml was added to methanol solution 1125 ml of 2-adamantyl acetic acid methyl ester 150 g (0.72 mol) and stirred at room temperature for 6 hours. Reaction mixture was concentrated in vacuo. Aqueous sodium bicarbonate solution was added to the residue and the mixture was washed with ether. Aqueous layer was adjusted to pH 1 by adding 12 N hydrochloric acid, extracted with ethyl acetate and dried with anhydrous sodium sulfate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27])=[CH2:20]>>[OH:31][C:24]1[CH:23]=[CH:22][C:21]([CH:19]=[CH:20][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(I)cc1
Reactant: C=Cc1ccc(O)c(C(=O)OC)c1
Product: COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Yield: 52 %

Procedure:
This compound was prepared analogously to Example 3 from 4-iodo-N-(3-methyl-2-pyridinyl)-benzenesulfonamide, prepared according to Example 2a, and methyl 5-ethenyl-2-hydroxybenzoate prepared according to Example 3a. Yield 52%.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[C:8]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OCc2ccccc2)=C(C)C1=O
Yield: 48.9 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (0.55 g, 1.21 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (1.67 g, 3.03 mmol) at room temperature, the solution was stirred at room temperature for 2 hours. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.250 g, 0.592 mmol, 49%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1

Procedure:
N-(6-Bromo-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 6-bromo-pyridin-2-ylamine (1.0 g, 5.8 mmol) in a manner analogous to Step 2a. The product of the reaction was isolated as a yellow solid. 1H NMR (400 MHz, CDCl3, δ, ppm): 12.03 (br s, 1H), 8.81 (d, J=8.0 Hz, 1H), 8.06 (br s, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H). MS=306 (MH)+. 12b) 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from N-(6-bromo-2-pyridinyl)-N′-carboethoxy-thiourea (1.8 g, 5.9 mmol) in a manner analogous to Step 2b. The product was isolated as an off-white solid (0.71 g, 56%). MP=203-205° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 7.40-7.32 (m, 2H), 7.23-7.20 (m, 1H), 6.26 (br s, 2H). MS=215 (MH)+. 12c) [5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 4-(4-bromo-phenyl)-morpholine (101.0 mg, 0.4172 mmol) in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.018 g, 12%). MP=247-249° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.28-8.24 (m, 2H), 8.15-8.11 (m, 2H), 7.55-7.51 (m, 2H), 7.49-7.44 (m, 2H), 7.04-7.01 (m, 1H), 6.96-6.91 (m, 2H), 6.68 (s, 1H), 3.90-3.85 (m, 4H), 3.15 (s, 3H), 3.14-3.10 (m, 4H). MS=450 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10][C:9]2=O)=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[O:27]=[C:28]1[N:32](CO)[C:31](=[O:35])[CH2:30][N:29]1[CH2:36][C:37]#[CH:38]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:12]([CH:13]([CH3:14])[CH3:15])[C:11]([O:10][CH2:9][N:32]2[C:31](=[O:35])[CH2:30][N:29]([CH2:36][C:37]#[CH:38])[C:28]2=[O:27])=[O:16])=[CH:6][CH:7]=1
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: C#CCN1CC(=O)N(COC(=O)C(Nc2ccc(Cl)cc2)C(C)C)C1=O
Reaction time: 20 h

Procedure:
To a solution of 3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione (1.32 mmol) and dimethylaminopyridine in 5 ml of dry tetrahydrofuran is added a solution of (2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol (1.26 mmol) in 3 ml of dry tetrahydrofuran. The reaction mixture is stirred for about 20 hours, under dry air, and then diluted with ether followed by washing with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. After drying over calcium sulfate, solvent is evaporated. The crude product is chromatographed on a rotary chromatograph eluting with 15% ether/hexane to give (2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(4-chlorophenylamino)-3-methylbutanoate.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1.[CH3:10][NH2:11]>C(O)C>[CH3:10][NH:11][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1
Reactant: CN
Reactant: CN1CCCC(CCl)C1
Solvent: CCO
Product: CNCC1CCCN(C)C1

Procedure:
A solution of 3-(chloromethyl)-1-methylpiperidine (9.2 g, 50 mmol) (U.S. Pat. No. 6,184,338, example 5) and 33% methylamine in ethanol (60 mL) in ethanol (30 mL) was heated in a sealed vessel at 100° C. for 17 hours. The reaction mixture was concentrated in vacuo and diluted with water before being extracted into dichloromethane and dried over magnesium sulphate. The reaction mixture was filtered and concentrated in vacuo to yield the title product, 8.2 g.
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:8]([CH3:9])[CH2:7][CH2:6][N:5]1[C@@H:10]1[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][C:12]([CH3:23])([CH3:22])[C@H:11]1[OH:24])#[N:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(OCC)(=O)C>[C:25]([O:24][C@H:11]1[C@H:10]([N:5]2[CH2:6][CH2:7][N:8]([CH3:9])[C:4]2=[N:3][C:1]#[N:2])[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][C:12]1([CH3:22])[CH3:23])(=[O:27])[CH3:26]
Reactant: CN1CCN([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1=NC#N
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](N2CCN(C)C2=NC#N)c2cc(C#N)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of trans-4-(2-cyanoimino-3-methylimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.95 g) in dry pyridine (9.5 ml) was added acetic anhydride (0.68 ml) at ambient temperature. The reaction mixture was stirred for 21 hours and 20 minutes at ambient temperature and then diluted with ethyl acetate (90 ml). The resultant solution was washed successively with 10% hydrochloric acid (50 ml, 30 ml), water (50 ml), saturated aqueous sodium bicarbonate (50 ml), dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether, and recrystallized from ethanol to give trans-3-acetoxy-4-(2-cyanoimino-3-methylimidazolidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.57 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([CH3:12])=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:13]1[C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14]1>C(O)C>[CH2:1]([N:8]([CH2:14][C:15]1([OH:13])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1)[CH2:9][C:10]([CH3:12])=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: C=C(C)CNCc1ccccc1
Solvent: CCO
Product: C=C(C)CN(Cc1ccccc1)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A mixture of N-benzyl-2-methyl-prop-2-en-1-amine (0.57 g, 3.52 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.75 g, 3.52 mmol) in ethanol (4 mL) was heated at 80° C. in a sealed vial for 16 hours. The reaction mixture was cooled and concentrated in vacuo to give tert-butyl 4-[[benzyl(2-methylallyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (1.32 g, 100%) as a colorless oil. ESI-MS m/z calc. 374.5. found 375.7 (M+1)+; Retention time: 1.24 minutes (3 min run).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[CH:15][CH:14]=1)[CH2:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:25][C:21]1[CH:20]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C@@H:3]([NH:2][C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:18][CH:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)CC(C)C(=O)OCC
Yield: 82.1 %

Procedure:
To a solution of (4S)-ethyl 4-amino-5-(3′-chlorobiphenyl-4-yl)-2-methylpentanoate hydrochloride salt (600 mg, 1.74 mmol) in DMF (13.1 mL) is added TEA (0.25 mL, 1.82 mmol) and ethyl 2-chloro-2-oxoacetate (0.19 mL, 1.74 mmol) at room temperature. After stirring this reaction for 1 hour at room temperature, the reaction is quenched with H2O, and diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography (eluent: heptane/EtOAc=70:30 to 50:50) to give (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (637 mg). HPLC retention time=1.66 minutes (condition A); MS 446.5 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH:14]([CH3:16])[CH3:15])[CH3:3].[NH:17]1C=CN=[CH:18]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:14]([CH3:16])[CH3:15])[CH:1]=[CH:18][N:17]=[CH:3]1
Reactant: CC(C)c1[nH]c2ccccc2c1CN(C)C
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Product: CC(C)c1[nH]c2ccccc2c1Cn1ccnc1
Yield: 26.6 %

Procedure:
3-(Dimethylaminomethyl)-2-isopropylindole (1.7 g.) and imidazole (0.6 g.) were heated at the reflux temperature in xylene (50 ml.) for a period of one hour. The solution was then cooled to room temperature (~20° C.) and petroleum ether (b.p. 60°-80° C.) was added until a faint cloudiness appeared. The resulting mixture was then allowed to stand at room temperature (~20° C.), whereupon the desired product soon crystallized from solution and was subsequently recovered by means of suction filtration. Recrystallization of the latter material from industrial methylated spirits (i.e., ethyl alcohol denatured with methanol) then gave pure 3-(imidazol-1-ylmethyl)-2-isopropylindole (yield, 0.5 g.), m.p. 241°-216° C.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[S:9][C:10](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[C:11](=[O:13])[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([NH:7][C:8]1[S:9][C:10](=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[C:11](=[O:13])[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NC[C@H](O)COc1ccccc1
Reactant: CCCCCCNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Product: CCCCCCNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 1-[4-(2-hexylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 32) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1 as a yellowish solid; mp 182-184° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ0.87(t, J=6.5 Hz, 3 H), 1.20-1.40 (m, 10 H), 1.50-1.65 (m, 2 H), 1.80-1.95 (m, 2 H), 2.60-4.00(m, 10 H), 6.85-6.95(m, 3 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.35 (m, 2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.45 (s, 1 H), 9.62 (brs, 1 H); MS (ES) m/z: 269.1 ((M+2H)2+, 100%), 537.1(MH+, 20%); HRMS Calcd. for C30H41N4O3S (MH+): 537.2899. Found: 537.2875.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[O:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[O:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)o1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C#CC=C2CCN(c3ccc([N+](=O)[O-])o3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of the Compound of Example 3 (100 mg, 0.47 mmol), 2-bromo-5-nitrofuran (98 mg, 0.51 mmol) and potassium carbonate (72 mg, 0.52 mmol) in DMF (2 mL) was stirred at r.t. for 4 h. Afterwards, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography eluting with Petroleum Ether-EtOAc 6:4 affording the title product (94 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: COc1ccc2ccccc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2ccccc2c1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
A solution of 2-methoxynaphthalene (20.0 g, 120 mmol) and 4-fluorobenzoyl chloride (15 ml, 126 mmol) in methylene chloride (200 ml) was cooled in an ice bath under nitrogen and aluminum chloride (18.5 g, 129 mmol, 1.1 equiv.) was added portionwise over 10 minutes. The reaction mixture was stirred at room temperature for 3 h and then poured into 2N HCl (500 ml). The product was extracted into methylene chloride, and washed with brine, and dried over sodium sulfate. The organic layer was concentrated in vacuo to give 34.6 g of 1-(4-fluorobenzoyl)-2-methoxynaphthalene as a solid (97% yield) which was used in the next step without further purification.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[C:16](=[O:29])[C:17]4[N:18]=[CH:19][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:21]=4[N:22]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:38].[Na+].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:15]2[C:16](=[O:29])[C:17]3[N:18]=[CH:19][N:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:21]=3[N:22]=[C:14]2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:38])[NH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:31][CH:32]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(-c2ccc(-c3nc4c(ncn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1ccc(-c2ccc(-c3nc4c(ncn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)c[nH]1
Temperature: 100 °C

Procedure:
A solution of 2-[4-(6-amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (10 mg, 0.02 mmol) in acetonitrile (0.4 mL) and H2O (0.4 mL) was treated with NaNO2 and 5 μL of concentrated H2SO4. The reaction mixture was heated at 100° C. for 1 h. The reaction was allowed to cool to room temperature and neutralized with aqueous Na2CO3. The reaction was diluted with H2O and extracted with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated. The resulting crude material was purified by preparative LCMS to provide the title compound 1-(4-chloro-phenyl)-2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one_as a white solid. 1H NMR (CDCl3) δ (ppm) 8.21 (s, 1H), 8.01 (dd, 1H), 7.81 (d, 1H), 7.58 (apparent t, 2H), 7.49 (m, 1H), 7.39 (d, 2H), 7.33 (m, 3H), 7.14 (d, 2H), 6.98 (d, 1H); HPLC-MS calculated for C28H18ClN5O2 (M+H+): 492.1. Found: 492.1.
Reaction SMILES: [Br:1]Br.N1C=CC=CC=1.[C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)#[N:10]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:15]1[CH:16]=[N:17][C:18]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:9]#[N:10])=[CH:20][CH:19]=2
Reactant: N#Cc1ccc2ncccc2c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1ccc2ncc(Br)cc2c1
Reaction time: 2 h

Procedure:
In an amount of 37.8 mg of 6-cyanoquinoline (Justus Liebigs Ann. Chem., 1966, 699, 98-106) was dissolved in 1 ml of carbon tetrachloride, added with 13 μl of bromine, and then stirred under reflux. After 2 hours, the reaction mixture was added with 20 μl of pyridine, and further stirred for 23 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate (4:1)) to obtain 34.8 mg of the title compound.