Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:19](=[O:21])[CH3:20])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(Cl)ccc2n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazin-2-amine (18 g, 106.5 mmol) in DCM (180 mL) was added triethylamine (10.8 g, 106.5 mmol), DMAP (1.32 g, 1.06 mmol), and acetic anhydride (6 g, 106.5 mmol) sequentially at rt. The reaction mixture was stirred for 5 h at rt and the precipitate was filtered and washed with 50 mL of methanol to afford the title compound (15 g, 66%). 1H NMR (DMSO-d6, 300 MHz): δ 7.3 (d, 1H), 8.02 (d, 1H), 8.25 (s, 1H). LCMS (M+1) 211 (99%).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(#N)C.C(O)C.C(N(CC)CC)C>[CH2:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51][CH2:52][N:43]1[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:13]([C:5]1[S:6][C:7]2[N:12]3[C:3](=[CH:2][N:1]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH:4]=1)=[O:15]
Reactant: NCCCCN1CCc2ccccc2C1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCCCCN1CCc2ccccc2C1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.76 g (9.18 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added a solution of 1.90 g (6.85 mM) of 2-(4-aminobutan-1-yl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride and 4.0 ml (28.7 mM) of triethylamine in ethanol (10 ml) and the mixture was further stirred for one hour. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 30%) to provide the title compound as red-purple amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH3:21][N:22]([CH3:39])[CH2:23][CH2:24][CH2:25][N:26]([CH3:38])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([N:26]([CH2:25][CH2:24][CH2:23][N:22]([CH3:21])[CH3:39])[CH3:38])=[C:28]([C:34]([F:35])([F:36])[F:37])[CH:29]=1)=[O:20]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Reactant: CN(C)CCCN(C)c1ccc(N)cc1C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCCN(C)c1ccc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2Cl)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 16.1) and 4-[(3-dimethylamino-propyl)-methyl-amino]-3-trifluoromethyl-phenylamine (Step 5.1). Title compound: ES-MS: 544.9 [M+H]+; single peak at tR=3.66 min (System 1); Rf=0.28 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [CH:1](NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]([CH:19]1[N:22]([Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:21](=[O:30])[CH2:20]1)[CH:17]=[CH2:18].IC>O1CCCC1.CCCCCC.C(O)(=O)C>[CH2:16]([CH:19]1[N:22]([Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[C:21](=[O:30])[CH:20]1[CH3:1])[CH:17]=[CH2:18]
Reactant: C=CCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Reactant: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: CC(=O)O
Product: C=CCC1C(C)C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
N-Isopropylcyclohexylamine (12.4 g) in dry tetrahydrofuran (300 ml) was treated with 2 M n-butyllithium in n-hexane (44 ml) at -78° under argon. After five minutes 4-allyl-1-t-butyldimethylsilylazetidin-2-one (9.0 g) in dry tetrahydrofuran (100 ml) was added. Thirty minutes later iodomethane (70 ml) was added. The solution was stirred at -78° for 30 minutes and at room temperature for 2 hours, after which acetic acid (5.0 ml) was added. The solution was evaporated and partitioned between ethyl acetate and water. The organic phase was separated, dried (Na2SO4), evaporated and chromatographed on silica gel 60 (230 mesh) eluting with ethylacetate:petroleum ether (60-80) 1:3 to give as a mixture of two isomers 4-allyl-1-t-butyldimethylsilyl-3-methylazetidin-2-one (8.0 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]([CH2:9][OH:10])[CH2:6][CH:7]=[CH2:8].[CH3:19][C:20]1C=CC(S(O)(=O)=O)=C[CH:25]=1.COC(OC)(C)C>CC(C)=O>[OH:10][CH2:9][C@H:5]([CH2:6][CH:7]=[CH2:8])[CH2:4][C@H:3]1[CH2:2][O:1][C:20]([CH3:25])([CH3:19])[N:11]1[C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18]
Reactant: C=CC[C@@H](CO)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Yield: 956.1 %

Procedure:
To a solution of tert-butyl (2S,4R)-1-hydroxy-4-(hydroxymethyl)hept-6-en-2-ylcarbamate (6.8 g, 26.2 mmol) in acetone (150 mL), PTSA (0.45 g, 2.62 mmol) was added. The reaction mixture was cooled to −20° C. followed by the addition of 2,2-dimethoxypropane (4.1 g, 39.4 mmol). The resulting mixture was stirred and allowed to warm to rt for 1 hr. TEA (0.5 mL) was then added and stirred for another 5 min. The solvent was removed under reduced pressure. The residue was dissolved in Et2O (300 mL), washed with 1 N HCl (80 mL), sat. aq. NaHCO3 (80 mL), brine (80 mL) successively, and dried, filtered, and concentrated under vacuum to give crude (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (7.5 g, 96%). It was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[C:9]1[N:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([NH:28]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.CCOC(C)=O>Br.C1C=CC=CC=1>[NH2:28][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][N:21]([C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]3[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=3[N:10]=2)[CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)NC2CCCCN(c3nc4c(c(=O)n(C)c(=O)n4C)n3Cc3ccccc3)C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(nc(N3CCCCC(N)C3)n2Cc2ccccc2)n(C)c1=O

Procedure:
N-(1-(7-Benzyl-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl)azepan-3-yl)-4-methylbenzenesulfonamide (6C) (100 mg, 0.19 mmol) was dissolved in hydrobromic acid (48%, 5 ml) and benzene (0.07 ml), and phenol (61.4 mg, 0.65 mmol) was added. The mixture was heated to reflux for three hours, and after cooling 20 ml of EtOAc was added. The layers were separated, and the aqueous layer washed with 20 ml of EtOAc. pH was adjusted to 11 with 10M sodium hydroxide. The aqueous layer was extracted with diethyl ether (3×20 ml), and the combined organic layers were dried over sodium sulphate and the solvent was evaporated. The crude product was dissolved in 5 ml of DCM and 0.5 ml of trifluoroacetic acid was added. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=7.63 min). Evaporation of the solvent gave the title compound as an oil.
Reaction SMILES: O.[NH2:2][NH2:3].Br[C:5]1[C:6](=[O:14])[NH:7][C:8]([N:11]([CH3:13])[CH3:12])=[N:9][N:10]=1>O>[CH3:12][N:11]([CH3:13])[C:8]1[NH:7][C:6](=[O:14])[C:5]([NH:2][NH2:3])=[N:10][N:9]=1
Reactant: CN(C)c1nnc(Br)c(=O)[nH]1
Reactant: NN
Solvent: O
Product: CN(C)c1nnc(NN)c(=O)[nH]1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
With stirring, hydrazine monohydrate (1.44 ml, 30 mmol) was added at 25° C. to a solution of the bromide (X) (2.20 g, 10 mmol) in water (80 ml). The reaction mixture was heated to reflux, cooled to room temperature and, for crystallization, allowed to stand for several hours. The crystals were filtered off, washed with water and dried in the air, giving the hydrazine (XI) (1.08 g, 63%) as a white solid of melting point 264-266° C. (from ethanol): IR spectrum vmax (NaCl/nujol/cm−1) 3324s, 3301s, (NH), 1641s (C═O), 1575s, 1516s, 1397s, 1304w, 1260w, 1204w, 1165w, 1133w, 1068w, 1050s, 1005w, 923s, 833w, 786s, 709s, 683s; NMR spectrum: δH (270 MHz, DMSO-d6): 11.25 (2H, bs, NH2), 7.18 (1H, bs, NH), 2.96 (6H, s, NCH3);
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:40])=[O:4])=[CH:12][CH:11]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.090 mL, 0.090 mmol) was added to a solution of (E)-[4′-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 53-(1); 15.3 mg, 0.030 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (7.0 mg, 47%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:26]1(O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCCCC2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and cyclohexanol in analogy to Example 9c): MS (ISN): 442.3 (M−H)−; MS (ISP): 444.2 (M+H)+, 344.1 ((M-Boc)+H)+ (100%).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][NH:16]C(OCC2C=CC=CC=2)=O)[C@@H:10]([CH2:28][CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[C:9]1=[O:39])(C)(C)C>FC(F)(F)C(O)=O.CO.[C].[Pd]>[NH2:16][CH2:15][C:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9](=[O:39])[C@@H:10]1[CH2:28][CH2:29][CH2:30][NH2:31])=[O:27]
Reactant: CC(C)(C)OC(=O)CN1CCN(C(=O)CNC(=O)OCc2ccccc2)[C@@H](CCCNC(=O)OC(C)(C)C)C1=O
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NCCC[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 ml of trifluoroacetic acid was dissolved 500 mg of (S)-4-benzyloxycarbonylaminoacetyl-3-(3-t-butoxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid t-butyl ester. The solution was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure to leave an oily product, which was dissolved in 10 ml of methanol. To the solution was added 10 mg of 10% palladium-carbon. The mixture was stirred for one hour at room temperature under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to leave a crude product of (S)-4-aminoacetyl-3-aminopropyl-2-oxopiperazine-1-acetic acid. This product was dissolved in a mixture of 10 ml of water and 10 ml of dioxane. To the solution was added 400 mg of sodium hydrogen carbonate. Subsequently, 420 mg of 3-(4-carboxyphenylamino)-1,2,4-oxadiazolin-4H-5-one produced in Reference Example 25 and 250 mg of N-hydroxysuccinimide were dissolved in 5 ml of dimethylformamide. To the solution was added 450 mg of dicyclohexyl carbodiimide. The mixture was stirred for 3 hours at room temperature, then concentrated under reduced pressure to leave an oily substance. This substance was dissolved in 5 ml of dioxane, and added to the solution of (S)-4-aminoacetyl-3-aminopropyl-2-oxopiperazine-1-acetic acid prepared as above. The mixture was stirred for 6 hours at room temperature. The reaction mixture was neutralized with 1N HCl, then concentrated under reduced pressure to give a crude product, followed by purification by means of a sephadex LH-20 column to afford 230 mg of the title compound as a colorless amorphous powdery product.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: COc1cccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-methoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.09 min; [M+H]+=388.21.
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[CH:10]1[CH:15]=[N+:14]([C@@H:16]2[O:20][C@H:19]([CH2:21][O:22][P:23]([O:26][P:27]([O:30][CH2:31][C@H:32]3[O:36][C@@H:35]([N:37]4[C:41]5[N:42]=[CH:43][N:44]=[C:45]([NH2:46])[C:40]=5[N:39]=[CH:38]4)[C@H:34]([O:47][P:48]([OH:51])([OH:50])=[O:49])[C@@H:33]3[OH:52])([OH:29])=[O:28])([OH:25])=[O:24])[C@@H:18]([OH:53])[C@H:17]2[OH:54])[CH:13]=[C:12]([C:55]([NH2:57])=[O:56])[CH:11]=1.[Cl-].[Mg+2].[Cl-].P(OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O)(O)(O)=O>>[CH:43]1[N:44]=[C:45]([NH2:46])[C:40]2[N:39]=[CH:38][N:37]([C@@H:35]3[O:36][C@H:32]([CH2:31][O:30][P:27]([O:26][P:23]([O:22][CH2:21][C@H:19]4[O:20][C@@H:16]([N:14]5[CH:13]=[C:12]([C:55]([NH2:57])=[O:56])[CH2:11][CH:10]=[CH:15]5)[C@H:17]([OH:54])[C@@H:18]4[OH:53])([OH:25])=[O:24])([OH:29])=[O:28])[C@@H:33]([OH:52])[C@H:34]3[O:47][P:48]([OH:51])([OH:50])=[O:49])[C:41]=2[N:42]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
The crude enzyme solution was added to a reaction mixture comprising 50 mmol/l Tris/HCl (pH 7.5), 0.5 mmol/l NADP, 10 mmol/l magnesium chloride and 2 mmol/l 6-phosphogluconic acid to make up to 1.5 ml. The resulting mixture was subjected to reaction in a 1-ml cuvette at 30° C. and the increase in the absorbance was measured at 340 nm. On the basis of the molar extinction coefficient of NADPH (6220), the amount of NADPH formed per minute was calculated. GND specific activity was expressed in terms of the amount of NADPH formed per mg of protein per minute.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17](O)=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.F[B-](F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]1[NH:31][C:26]2[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[CH:28][C:27]=2[N:30]=1)[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2nc([C@H](CC(C)C)NC(=O)OCc3ccccc3)[nH]c2c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a mixture of N-benzyloxycarbonyl-L-leucine (20 mmol, 5.3 g), 4-methoxy-1,2-phenylenediamine dihydrochloride (4.22 g, 20 mmol) and O-benzotriazole-N,N,N',N'-tetramethyl-uronium-tetrafluoroborate (TBTU) (6.58 g, 20.50 mmol) in 15 mL DMF cooled in an ice bath was added diisopropylethylamine (14 mL, 80 mmol). After stirring for 2 hours, ethyl acetate was added and the solution was washed with saturated NaHCO3 3 times and brine 3 times, dried (MgSO4), and concentrated. The crude product was dissolved in 30 mL acetic acid and the solution was heated at 65° C. for 2 hours. Acetic acid was removed by concentration under reduced pressure and the residue was purified on a silica gel column using methanol (3%)-methylene chloride as eluent to give 5.5 g (80%) product. m.p. 73°-77° C. ES-MS: calcd M+1 368.2; found 368.3.
Reaction SMILES: [CH2:1]([C@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:19])[CH2:5]1)[CH:2]=[CH2:3].CN(C=[O:30])C>Cl[Pd]Cl.Cl[Cu]>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]([N:7]2[CH2:8][CH2:9][C@:4]([CH2:1][C:2](=[O:30])[CH3:3])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:5][C:6]2=[O:19])[CH3:11])=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Product: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
In a three-necked flask, a mixture of PdCl2 (180 mg, 1 mmol) and CuCl (500 mg, 5 mmol) in aqueous DMF (15 mL of DMF and 5 mL of water) was stirred under an oxygen atmosphere for 1 h at rt, and (S)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-phenylpiperidin-2-one (2 g, purity=65%, 3.3 mmol) was added. The mixture was stirred vigorously under an oxygen atmosphere for 24 h at rt. The reaction mixture was quenched with aq NaHCO3 solution. The organic phase was washed with brine, and dried over NaSO4. After evaporation of the solvent, the residue was purified by prep TLC to give (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-oxopropyl)-4-phenylpiperidin-2-one (400 mg, 29.6%))
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19](=[O:36])[N:20]([C:27]2[O:35][C:31]3=[CH:32][CH:33]=[CH:34][C:30]3=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19](=[O:36])[N:20]([C:27]2[O:35][C:31]3=[CH:32][CH:33]=[CH:34][C:30]3=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][C:15]([C:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(Br)cc2)cc1
Reactant: OB(O)C1=CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 130 °C
Yield: 102.1 %

Procedure:
A mixture of 4-[2-(4-benzofuran-2yl-phenylcarbamoyl)-2-(4-bromo-phenyl)-ethyl]-benzoic acid methyl ester (0.4 g, 0.74 mmol), cyclohexen-2-ylboronic acid (0.23 g, 1.85 mmol), PdCl2(o-tolylphosphine) (75 mg, 0.096 mmol), and Na2CO3(390 mg, 3.70 mmol) in DME/EtOH/H2O (4:2:1)(17.5 mL) was heated in an oil bath at 130° C. for 2 h, cooled to rt, filtered and washed with EtOAc (20 mL). The solvent was removed under reduced pressure. The crude mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel, eluting with ethyl acetate:hexanes (3:2) to afford 4-[2-(4-benzofuran-2-yl-phenylcarbamoyl)-2-(4-cyclohex-1-enyl-phenyl)-ethyl]-benzoic acid methyl ester as a white solid (0.42 g). 1H NMR (300 MHz, CDCl3): δ 10.23 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.54-7.65 (m, 4H), 7.21-7.34 (m, 8H), 6.10 (bt, 1H), 4.02 (m, 1H), 3.78 (s, 3H), 3.45 (dd, J=8.7, 13.5 Hz, 1H), 3.04 (dd, J=6.6, 13.5 Hz, 1H), 2.25-2.40 (m, 2H), 2.10-2.20 (m, 2H), 1.64-1.72 (m, 2H), 1.54-1.59 (m, 2H); LC-MS m/z=556 [C37H33NO4+H]1; TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate/hexanes (2:1); R1=0.45.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][C:21]([F:24])([F:23])[F:22])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[CH:3]=[CH:4][C:5]([O:20][C:21]([F:24])([F:23])[F:22])=[C:6]([CH:8]3[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]3=[O:19])[CH:7]=2)=[CH:28][CH:27]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC1(C)OC(C)(C)C(=O)C(c2cc(Br)ccc2OC(F)(F)F)C1=O
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(Oc3ccc(Cl)cc3)ccc2OC(F)(F)F)C1=O
Temperature: 160 °C

Procedure:
To a mixture of 4-(5-bromo-2-trifluoromethoxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.254 g, 0.62 mmol), 4-chlorophenol (0.400 g, 3.11 mmol), cesium carbonate (0.440 g, 1.25 mmol), copper (II) trifluoromethanesulfonate (11 mg, 0.03 mmol) and powdered 4 Å molecular sieves (0.40 g) is added anhydrous toluene (3.5 ml). After flushing with nitrogen the mixture is heated at 160° C. for 1 hour under microwave irradiation, then cooled to room temperature and quenched with 2M aqueous hydrochloric acid. The crude product is extracted with dichloromethane (×3), and the organic fractions are combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by preparative reverse phase HPLC affords 4-[5-(4-chlorophenoxy)-2-trifluoromethoxyphenyl]-2,2,6,6-tetramethylpyran-3,5-dione as a white powder.