Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:25])=[C:5]([CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6]=1[C:7](O)=[O:8].[Cl-].[CH3:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]([NH3+:39])[CH3:38])=[CH:33][CH:32]=1)=[O:30]>>[Cl:1][C:2]1[S:3][C:4]([Cl:25])=[C:5]([CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6]=1[C:7]([NH:39][C@H:37]([C:34]1[CH:35]=[CH:36][C:31]([C:29]([O:28][CH3:27])=[O:30])=[CH:32][CH:33]=1)[CH3:38])=[O:8]
Reactant: O=C(O)c1c(Cl)sc(Cl)c1C(OC1CCCCO1)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Agent: [Cl-]
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2C(OC2CCCCO2)c2cccc(Cl)c2)cc1

Procedure:
2,5-Dichloro-4-[(3-chlorophenyl)(tetrahydro-2H-pyran-2-yloxy)methyl]thiophene-3-carboxylic acid from Example 8, Step 3 (207 mg, 0.491 mmol) was reacted with (1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride from Example 1, Step 9 under conditions similar to Example 1, Step 10. The crude product was purified by Combi Flash chromatography system (2-8% EtOAc/toluene in 20 min.) to afford the desired product as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:25][C:19]1[CH:18]=[C:17]2[C:22]([C:23](=[O:24])[C:14]([CH2:13][NH:12][C:5](=[O:6])[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=3)=[CH:15][N:16]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
A 10 mL round bottom flask was charged with 3,5-difluorobenzoyl chloride (78.0 mg, 0.442 mmol) and anhydrous methylene chloride (5 mL) and was treated with 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (49.8 mg, 0.175 mmol), triethylamine (87.1 mg, 0.12 mL, 0.861 mmol), and catalytic N,N-(dimethylamino)pyridine (DMAP) (one spatula tip). The flask was capped with a glass stopper and the reaction stirred at room temperature over the weekend. The reaction was partitioned between methylene chloride (25 mL) and water (25 mL). The organic portions were dried over magnesium sulfate, filtered and rinsed with methylene chloride, concentrated on a rotary evaporator, and briefly dried on a vacuum pump. The material was then purified via Analogix Intelliflash 280 chromatography using a 12 g silica gel column and a 1%-5% MeOH/CH2Cl2 gradient elution. Two columns were required to isolate the desired product from the bis-acylation side product. Fractions containing the two products were separately combined and concentrated. The second product to elute was the desired product N-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,5-difluoro-benzamide, isolated as an off-white solid (44 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (t, J=5.14 Hz, 1H) 8.27 (d, J=8.66 Hz, 1H) 8.03 (s, 1H) 7.38-7.73 (m, 9H) 6.90 (d, J=1.81 Hz, 1H) 4.37 (d, J=5.24 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([NH:32][CH3:33])[CH2:28][CH2:27]2)[CH2:24][CH2:23]1.C(N(CC)CC)C.C([O-])(=O)C>C(#N)C>[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH3:33])[C:18](=[O:20])[CH2:17][O:16][C:12]3[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:21])[N:11]=3)[CH2:28][CH2:27]2)[CH2:23][CH2:24]1
Reactant: CNC1CCN(CC2CC2)CC1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC3CC3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
Compound 9 (100 mg), 1-(cyclopropylmethyl)-N-methylpiperidine-4-amine (56.6 mg) and triethylamine (234 μL) were suspended in acetonitrile (2 mL). While the suspension was cooled with ice, a 50% propane phosphonic acid anhydride ethyl, acetate solution (273 mg) was added portionwise. The equipment used to add the 50% propane phosphonic acid anhydride ethyl acetate solution was thoroughly washed with acetonitrile (0.5 mL) and was stirred at room temperature (20 to 30° C.) overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:methanol=30:1) to give 79 mg (52% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:21]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@H](NC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (115 g, 4.26 mmol) in CH2Cl2 (25 mL) at 0° C. under inert atmosphere was slowly added a solution of benzyl(S)-piperidin-3-ylcarbamate (1.0 g, 4.26 mmol) and triethylamine (1.18 mL, 8.52 mmol) in CH2Cl2 (10 mL). The reaction was allowed to warm to room temperature and was then quenched with water. The mixture was extracted with CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated to obtain benzyl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (2.03 g). This material was used without further purification. LC/MS: m/z 469.1 (M+H)+ at 2.86 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[S:29])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Yield: 63.4 %

Procedure:
To 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one (9 g) in toluene (175 ml), under nitrogen, was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (12.6 g). The mixture was refluxed for 1 hr and concentrated under reduced pressure. Recrystallization of the residue from chloroform:hexane afforded 6 g (63%) of product, mp 196°-197° C.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:5])[CH3:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>ClCCl>[Br:1][CH2:2][CH:3]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH3:4]
Reactant: C1=COCCC1
Reactant: CC(O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(CBr)OC1CCCCO1

Procedure:
5.0 ml of 1-bromo-2-propanol was dissolved in 40 ml of dry dichloromethane, and 7.6 ml of 2,3-dihydropyran and 237 mg of dry p-toluenesulfonic acid were added thereto. The mixture was reacted at room temperature for 5 hours and then diluted by an addition of 250 ml of chloroform. The mixture was washed sequentially with a 4% sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. Then, the chloroform layer was dried over anhydrous magnesium sulfate. After filtering the inorganic salt off, the filtrate was concentrated under reduced pressure to obtain a brown syrup. This syrup was purified by silica gel flash column chromatography (130 g of Wacogel C-300 and eluted with hexane/ethyl acetate (15/1). The eluate containing the desired product was collected and concentrated under reduced pressure to obtain 11.3 g of 1-bromo-2-(tetrahydropyran-2-yl)oxypropane as a colorless transparent volatile syrup.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][O:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]#[CH:49])=[CH:44][CH:43]=1.C(N(CC)CC)C>ClCCl.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.[Cu]I>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:10]1[O:11][CH2:12][CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:49]#[C:48][C:45]3[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CCO1
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2ccc(C3CCOC(c4c(F)cccc4F)=N3)cc2)cc1

Procedure:
In 2 mL of dichloromethane, the product of Step C (0.07 g) was combined with tetrakis(triphenylphosphine)palladium(0) (0.010 g), copper(I) iodide (0.006 g), triphenylphosphine (0.006 g), (4-fluorophenyl)acetylene (prepared by the method of A.D. Allen and C. D. Cook, Can. J. Chem. (1963), 41, 1084; 0.15 g), and triethylamine (2 mL) and the mixture heated at reflux until thin layer chromatographic analysis showed consumption of starting material. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the title product, a compound of this invention, as a solid melting at 95°-110° C. (material prepared on larger scale, identical by 1H NMR spectroscopy, was recrystallized from ethyl acetate/hexane to give a solid melting at 102°-104° C.). 1H NMR (CDCl3) δ2.0 (m, 1H), 2.4 (m, 1H), 4.3 (m, 1H), 4.5 (m, 1H), 4.8 (m, 1H), 6.9-7.1 (m,4H), 7.3-7.4 (m,3H), 7.5-7.6 (m,4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2].[Br:25]Br>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:21])([F:22])[F:20])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=[C:12]([Br:25])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cccc2c1OCC2)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)cc2c1OCC2)C(F)(F)F
Yield: 94.9 %

Procedure:
To a solution of 10 g (29 mmol) of 4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester in 20 mL of acetic acid (HOAc) was added dropwise a solution of 1.55 mL (30 mmol) of bromine in 10 nL of HOAc. The reaction was monitored by proton NMR. An additional 0.5 mL of Br2 was added. The mixture was diluted with saturated aqueous sodium bicarbonate and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 11.7 g (95%) of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester.
Reaction SMILES: C1(O[C:8]#[N:9])C=CC=CC=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[N:25][CH:24]=[C:23]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])[C:18]=1[C:19]([NH:21][NH2:22])=[O:20]>CS(C)=O>[NH2:9][C:8]1[O:20][C:19]([C:18]2[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])=[CH:26][N:25]=[CH:24][C:23]=2[NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[N:21][N:22]=1
Reactant: N#COc1ccccc1
Reactant: NNC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Solvent: CS(C)=O
Product: Nc1nnc(-c2c(Nc3ccc(I)cc3F)cncc2-c2ccccc2F)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
Phenyl cyanate (6 mg, 0.05 mmol) was added to a solution of 3-(2-fluoro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (22 mg, 0.05 mmol) in DMSO (1 mL), and stirred overnight at room temperature. The reaction solution was quenched with H2O. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to afford the desired product (15 mg, 65%). LC-MS (M+H=492, obsd.=492). 1H NMR: δ 8.78 (s, 1H), 8.43 (d, 1H), 8.11 (d, 1H), 7.73 (dd, 1H), 7.44 (m, 3H), 7.30 (m, 3H), 7.14 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][C@@H:7]1[C@@H:11]([CH2:12][Si:13]([CH3:21])([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([CH2:22][OH:23])=[CH:9][CH2:8]1)([CH3:4])[CH3:3].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:30].[Mg+2]>CO.C(OCC)(=O)C>[CH3:4][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][C@H:7]1[CH2:8][C@@H:9]2[C@@:10]([CH2:22][OH:23])([O:30]2)[C@@H:11]1[CH2:12][Si:13]([CH3:21])([CH3:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC=C(CO)[C@@H]1C[Si](C)(C)c1ccccc1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H]2O[C@@]2(CO)[C@@H]1C[Si](C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
To a cooled (0° C.), stirred solution of 44 (14 g, 37.23 mmol) in MeOH (50 mL) was added magnesium monoperoxyphthalate (MPPA, 80% pure, 27.62 g, 44.68 mmol) in six portions over a period of 1 hour, keeping the temperature <0° C. The reaction mixture was stirred at the same temperature for 4 hours to complete the reaction. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with saturated sodium bisulfite (200 mL), sodium hydroxide (0.5 N, 2×150 mL), brine (150 mL) and dried over magnesium sulfate. The organic layer was concentrated in vacuo to dryness to give the crude title compound (13.5 g, 92%)
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:41]=[C:40]4[C:36]([C:37]([NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])=[N:38][N:39]4COCC[Si](C)(C)C)=[CH:35][C:34]=3[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[C:56]1([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][C:33]=2[C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:28][CH:29]=2)[NH:39][N:38]=[C:37]3[NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccccc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccccc3)cc12
Yield: 83.3 %

Procedure:
10.1 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[6-[4-(phenylmethoxy)phenyl]-5-phenyl-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 40 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 100 cm3 of saturated sodium hydrogen carbonate solution and with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 2 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is dried (90 Pa; 45° C.) to give 650 mg of N-[5-phenyl-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][CH2:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]O[CH2:36][CH2:35]1>>[O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][C@H:3]1[CH2:36]/[CH:35]=[CH:34]/[C:38]1[CH:17]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](C/C=C/c2ccccc2)C(=O)N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of protected pyroglutamate 8a (1.023 g, 3.20 mmol) in 15 mL THF at −78° C., was added LiHMDS (1M THF, 3.20 mL, 3.20 mmol). The mixture was stirred at −78° C. for 1 h, then a solution of cinnamyl Br in THF (3 mL) was added. The mixture was stirred at −78° C. for 1.25 h, then was quenched with sat. NH4Cl. The mixture was diluted with H2O, then extracted with EtOAc (3×). The organic phase was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (15% EtOAc/hexanes) to afford 390 mg (28%) of 8b as a white solid. 1H NMR (300 MHz, CDCl3) δ7.43-7.22 (m, 10H), 6.46 (d, J=15.7, 1H), 6.18-6.06 (m, 1H), 5.33-5.20 (m, 2H), 4.50 (dd, J=9.3, 1.7, 1H), 2.88-2.63 (m, 1H), 2.45-2.33 (m, 1H), 2.24-2.12 (m, 2H), 1.38 (s, 9H); MS (ESI) 436.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:16])[C:9]([N:11]3[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:10][C:5]=2[O:4][CH:3]=1>[Pd].O1CCOCC1>[CH3:1][CH:2]1[C:6]2[CH:7]=[C:8]([CH3:16])[C:9]([N:11]3[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Cc1cc2c(C)coc2cc1-n1cccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-n1cccc1)OCC2C

Procedure:
A mixture of 8 g (37.9 mmole) of 3,5-dimethyl-6-(pyrrol-1-yl)-benzofuran, 1.6 g of 5% palladium on carbon and 80 ml of dioxane is hydrogenated at 35° and a pressure of 4 bar. To complete the reaction, 0.8 g, each time, of 5% palladium on carbon is added a further three times during hydrogenation. After a total of 100 hours, the catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo. Chromatography of the residue over silica gel (petroleum ether/methylene chloride) and distillation of the pure fractions in a bulb tube (120°/2.10-2 torr) yields 3,5-dimethyl-6-(pyrrol-1-yl)-2,3-dihydrobenzofuran in the form of a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:33]3[CH:34]=[CH:35][C:30]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:31][CH:32]=3)=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O)cc2)COC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Oc3ccc(Oc4ccccc4)cc3)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 7.5 %

Procedure:
To a solution of (S)-4-(4-Hydroxy-benzyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.250 g, 0.846 mmol), 4-Phenoxyphenyl-boronic acid (0.181 g, 0.846 mmol), and triethylamine (0.59 mL, 4.232 mmol) in anhydrous dichloromethane (DCM) (20.8 mL) at room temperature under an atmosphere of nitrogen was added copper (II) acetate (0.154 g, 0.846 mmol), and the resulting mixture was stirred at room temperature for about 60 hours. The reaction mixture was washed with 20 mL of water and 20 mL of DCM and filtered. The DCM layer was then extracted. The aqueous layer was re-extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvent was removed in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (0.030 g, 8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13]>>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1ccncc1
Product: O=C(Nc1ccncc1)c1cccc(Cl)c1
Yield: 52 %

Procedure:
Employing 0.18 g (1.9 mmol) of 4-amino-pyridine and 0.51 g, (2.9 mmol) of 3-chlorobenzoyl chloride in the procedure described above and elution with CHCl3/MeOH/Et3N (9.8:0.1:0.1) resulted in white crystals (52% yield).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:14][C:13](=[O:15])[CH:12]=[C:11]1[OH:16])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:16][C:11]1[CH:10]([CH2:9][OH:8])[O:14][C:13](=[O:15])[CH:12]=1
Reactant: O=C1C=C(O)C(COCc2ccccc2)O1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(O)C(CO)O1
Yield: 94.9 %

Procedure:
386.0 mg (1.75 mmol) of 5-benzyloxymethyl-4-hydroxyfuran-2(5H)-one (Aragon, D. T. et al., J. Org. Chem. 68, 3363-3365, 2003) are initially charged in 19.3 ml of ethanol, 38.6 mg (0.27 mmol) of Pd(OH)2/C (20%) are added and the mixture is hydrogenated at room temperature until the hydrogen uptake has stopped. Removal of the catalyst by filtration and evaporation of the solvent gives 216 mg (94.7% of theory) of 4-hydroxy-5-hydroxymethylfuran-2(5H)-one which can be used without further purification for a subsequent reaction.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]3[CH2:16][S:15](=[O:18])(=[O:17])[CH2:14][CH:13]3[CH:8]2[C:7]1=[O:19].Cl.[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[N:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:21].[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH:9]4[CH:12]5[CH2:16][S:15](=[O:18])(=[O:17])[CH2:14][CH:13]5[CH:8]4[C:7]3=[O:19])[CH2:32][CH2:33]2)[CH:25]=[N:24][CH:23]=1
Reactant: O=C1C2C3CS(=O)(=O)CC3C2C(=O)N1CCCCBr
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C2C3CS(=O)(=O)CC3C2C(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1
Reaction time: 8 h

Procedure:
A solution of 2.0 g of 5-(4-bromobutyl)tetrahydro-1H-thieno-[3',4':3,4]cyclobuta[1,2-c]pyrrole-4,6(3H,5H)dione 2,2-dioxide in 50 ml of dimethylformamide is added to a stirred solution 2.0 g (0.007 mol) of 1-(6-chloro-2-pyrazinyl)-piperazine hydrochloride and 4 ml of triethylamine. The reaction mixture is stirred overnight and the solvent is removed under vacuum. The residue is partitioned between water and methlene chloride. The methylene chloride extracts are combined, washed with brine and dried over anhydrous sodium sulfate. Filtration and roto-evaporation gives the crude free base. Preparative HPLC [silica gel; ethyl acetate:methylene chloride (9:1)] followed by evaporation of the appropriate fractions (TLC Rf=0.4), treatment with ethanolic hydrogen chloride and recrystallization from ethanol gives the title compound: m.p. 154°-157° C.