Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=3.C(C1NC=CN=1)(C1NC=CN=1)=O.[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C>[OH2:15].[CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14]([O:16][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=3.[N:32]1([CH2:31][CH2:30][O:29][C:14]([C:2]2[N:3]=[C:4]3[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]3[CH:1]=2)=[O:15])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1cn2c(ccc3ccccc32)n1
Reactant: OCCN1CCCCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: O
Product: O=C(OCCN1CCCCC1)c1cn2c(ccc3ccccc32)n1
Temperature: 80 °C

Procedure:
0.85 g of imidazo-[1,2-a]-quinoline-2-carboxylic acid was dissolved in 25 ml of dry DMF and then 0.72 g of carbonyl diimidazole was added with stirring. The temperature was raised to 80° C. for 15 minutes and 0.57 g of (2-hydroxyethyl) piperidine was then added. The mixture was stirred at 100° C. for 3 hours and was cooled to room temperature and filtered. Then, 50 ml of water were added dropwise to the filtrate and the precipitate was filtered off, washed with water and dried under vacuum. This solid was crystallized from ethyl acetate/petroleum ether to obtain 2-piperidinoethyl imidazo-[1,2-a]-quinoline-2-carboxylate hemihydrate melting at 147°-150° C.
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C@@:8]2([CH3:41])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH:26][C@H:27](C)[C:28](O)=[O:29])=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[C:9]2=[O:40])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:45]CC(N)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:28]([CH2:27][NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:43][CH:42]=3)([CH3:41])[C:9](=[O:40])[N:10]([C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)[C:11]2=[N:15][CH:14]=1)(=[O:17])=[O:18])=[O:25])(=[O:29])[NH2:45]
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: NCC(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)NCC(N)=O)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
(S)-1-[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (see Example 5) (0.25 g, 0.435 mmol) was dissolved in a mixture of CH2Cl2 (10 mL) and DMF (0.2 mL). To this solution, were added glycinamide hydrochloride (0.072 g, 0.653 mmol), TBTU (0.21 g, 0.653 mmol), and DIPEA (0.19 mL, 1.087 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl followed by saturated aq. NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica gel preparative thin layer chromatography using CH2Cl2-MeOH (95:5) as an eluent to afford 0.155 g of the title compound as a white foam (M+1, 630).
Reaction SMILES: C=O.[ClH:3].[Br:4][C:5]1[C:9]([Br:10])=[C:8]([Br:11])[S:7][CH:6]=1.[C:12](O)(=O)C>>[Cl:3][CH2:12][C:6]1[S:7][C:8]([Br:11])=[C:9]([Br:10])[C:5]=1[Br:4]
Reactant: Brc1csc(Br)c1Br
Reactant: CC(=O)O
Reactant: Cl
Agent: C=O
Product: ClCc1sc(Br)c(Br)c1Br
Temperature: 70 °C
Reaction time: 6 h

Procedure:
4.07 G. (50 mmol) of formalin (37%) and 40 ml. of concentrated hydrochloric acid were added to a solution of 10.2 g. (33.3 mmol) of 3,4,5-tribromothiophene in 20 ml. of acetic acid. The resulting mixture was warmed to 70° C. After 6 hrs., 4.07 g. of formalin were added and heating was continued overnight. The resulting mixture was cooled, poured on ice water and extracted with ether. The organic phase was washed twice with water, sodium bicarbonate and water, dried and evaporated to give crude 2-chloromethyl-3,4,5-tribromothiophene.
Reaction SMILES: C([O:5][CH2:6][CH2:7][O:8][NH:9][C:10]([C:12]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[F:30])=[C:20]([F:31])[C:15]2[N:16]=[CH:17][N:18]([CH3:19])[C:14]=2[CH:13]=1)=[O:11])(C)(C)C.C(#N)C.P(=O)(O)(O)O>C(O)C.O>[OH:5][CH2:6][CH2:7][O:8][NH:9][C:10]([C:12]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[F:30])=[C:20]([F:31])[C:15]2[N:16]=[CH:17][N:18]([CH3:19])[C:14]=2[CH:13]=1)=[O:11]
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NOCCOC(C)(C)C)cc21
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NOCCO)cc21
Temperature: 51.5 °C
Reaction time: 0.25 h

Procedure:
6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) monohydrate is added in 3 portions to a premixed solution of Acetonitrile and excess Phosphoric acid (85% aqueous solution) at internal temperature 20-25° C. After stirring for about 15 minutes, the suspension is heated to internal temperature 50-53° C. The suspension is maintained at this temperature for 6 hours, cooled to internal temperature 20-25° C. The mixture is then heated to internal temperature 35-37° C. and diluted with Ethanol-Water (3:1 v/v). EKNS and CEFOK are added, the reaction mixture is stirred approximately 15 minutes and filtered over a funnel coated with CEFOK. The filtrate is cooled to approximately 30° C. 3 N aqueous potassium hydroxide (KOH) is added to the cooled filtrate over a period of 90 minutes until a pH-value of about 8.1 is reached. The suspension is heated to internal temperature 60-63° C., stirred at this temperature for a period of about 2 hours, cooled to 20-23° C. over a period of about 45 minutes, filtered over a funnel, and dried at 50° C. pressure<100 mbar over a period of about 17 hours, providing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[F:20])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:5][CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[F:20])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:5][CH:4]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C(=O)c1ccc(F)c(-c2ccc(CCl)nn2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(F)c(-c2ccc(CN=[N+]=[N-])nn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
3-(6-(Chloromethyl)pyridazin-3-yl)-4-fluoro-N,N-dimethylbenzamide (470 mg, 1.60 mmol) was treated with NaN3 (312 mg, 4.80 mmol) and DMF (5 mL) and stirred at RT for 15 h. The reaction mixture was extracted with EtOAc and the organic layer was washed with water and brine (2×30 mL), dried over MgSO4, filtered and concentrated. Purification of the crude material by silica gel chromatography (30-100% EtOAc in hexanes) afforded 3-(6-(azidomethyl)pyridazin-3-yl)-4-fluoro-N,N-dimethylbenzamide (341 mg, 1.14 mmol, 71.0% yield) as a clear colorless film. MS (ESI, pos. ion) m/z: 301.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (1 H, dd, J=7.3, 2.1 Hz), 8.02 (1 H, dd, J=8.8, 1.6 Hz), 7.57-7.69 (2 H, m), 7.22-7.31 (1 H, m), 4.81 (2 H, s), 3.08 (3 H, s), 3.13 (3 H, s). 19F NMR (376 MHz, CDCl3) δ ppm −115.30 (1F, s).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C@H:19]1[CH2:29][CH2:28][C@H:27]([OH:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20]1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]1[CH2:29][CH2:28][C:27](=[O:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20]1
Reactant: O[C@H]1CC[C@H](c2cccc(F)c2F)Cc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2cccc(F)c2F)Cc2cccnc21
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (0.91 mL, 11 mmol) in dichloromethane (15 mL) at −65° C. was added DMSO (0.94 mL, 13 mmol), and the mixture was stirred for 30 min. A solution of racemic trans 6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (prepared according to the procedures described by Leahy, D. K et al Org. Lett. 2012, 14, 4938-4941, 365 mg, 1.33 mmol) in dichloromethane (3 mL) was added drop wise and the resulting solution was stirred at −65° C. for 30 min. Triethylamine (2.55 mL, 18.6 mmol) was added and the reaction mixture was gradually warmed to 23° C. over a period of 4 h, and then partitioned between water and dichloromethane. The organic layer was washed with water (3×), brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 35% ethyl acetate in petroleum ether to give the title compound as a racemic mixture. MS: m/z=274.2 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](F)=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=1)=[O:19].O>CS(C)=O.ClCCl>[C:6]([O:5][C:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([O:16][C:23]2[CH:24]=[CH:25][C:20]([C:18](=[O:19])[CH3:17])=[CH:21][C:22]=2[C:27]([F:28])([F:29])[F:30])[CH2:11]1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1ccc(OC2CCCN(C(=O)OC(C)(C)C)C2)c(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a suspension of sodium hydride (408 mg, 10.2 mmol) in DMSO (15 ml) was added 1-boc-3-hydroxypiperidine (2.00 g, 10.2 mmol) at 0° C. Stirring was continued for 30 min at 10° C. and 4-fluoro-3-(trifluormethyl)acetophenone (1.40 g, 6.79 mmol) was added dropwise. The reaction mixture was stirred at RT for 1 h and then transferred into water (200 ml) at 0° C. Dichloromethane (300 ml) was added. The organic phase was washed with water (200 ml) and dried over sodium sulfate. Evaporation and purification of the crude product by silica gel chromatography using ethyl acetate/heptane=1:1 gave the desired product (1.80 g, 68%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:39])[NH:7][C@@H:8]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]2[C:18]3[CH:31]=[CH:30][S:29][C:19]=3[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)[CH2:13][C@H:12]1[C:32](O)=[O:33])=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:40][C@@H:41]([CH2:50][CH2:51][CH3:52])[CH:42]([OH:49])[C:43]([NH:45][CH:46]1[CH2:48][CH2:47]1)=[O:44].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[C:1]([NH:5][C:6](=[O:39])[NH:7][C@@H:8]([C:35]([CH3:37])([CH3:38])[CH3:36])[C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]2[C:18]3[CH:31]=[CH:30][S:29][C:19]=3[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)[CH2:13][C@H:12]1[C:32]([NH:40][C@@H:41]([CH2:50][CH2:51][CH3:52])[CH:42]([OH:49])[C:43]([NH:45][CH:46]1[CH2:47][CH2:48]1)=[O:44])=[O:33])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc(-c3ccccn3)nc3sccc23)C[C@H]1C(=O)O)C(C)(C)C
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2nc(-c3ccccn3)nc3sccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)C(O)C(=O)NC1CC1

Procedure:
(2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidine-2-carboxylic acid (60) (1 mmol) was coupled with (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (1 mmol, as prepared in Reference A) in the presence of O (7 azabenzotriazol 1 yl) 1,1,3,3 tetramethyl-uronium hexafluorophosphate (HATU) (1.2 mmol) and diisopropylethylamine (4 mmol) in dichloromethane and N,N-dimethylformamide to give (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-4-(2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidine-2-carboxamide (61) as a crude solid after aqueous/organic extractive work up.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)=[CH:21][CH:22]=3)=[O:16])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([NH:14][CH:13]3[CH2:12][CH2:11][NH:10][CH2:9][CH:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:16])=[CH:18][N:19]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(-c3cccc(F)c3)nc2)C(c2ccc(F)cc2)C1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCNCC1c1ccc(F)cc1)c1ccc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(4-fluorophenyl)-4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate (348 mg, 0.71 mmol) in CH2Cl2 (5 mL) at 0° C. was added TFA (1.2 mL). After stirring overnight at rt the the reaction was diluted with toluene (5 mL) and then the solvent removed and the residue purified by chromatography (silica, 10% MeOH/DCM) to give the desired product, 6-(3-fluorophenyl)-N-[3-(4-fluorophenyl)piperidin-4-yl]nicotinamide. (168 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) □ ppm 8.87 (1H, d, J=2.0 Hz), 8.52 (1H, s), 8.04-8.15 (2H, m), 8.00 (2H, d, J=7.9 Hz), 7.58 (1H, d, J=6.1 Hz), 7.35 (4H, dd, J=9.0, 3.5 Hz), 7.08-7.22 (2H, m), 4.60-4.72 (1H, m), 3.81 (1H, t), 3.05-3.27 (4H, m), 1.91 (1H, s). LC/MS=(M+H)=394.1 observed, 394.17 expected.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=1[C:17]([OH:19])=O.[O:20]=[C:21]1[CH:26]([N:27]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:25][CH2:24][C:23](=[O:43])[NH:22]1>>[O:20]=[C:21]1[CH:26]([N:27]2[C:17](=[O:19])[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[C:11]2=[O:13])[CH2:25][CH2:24][C:23](=[O:43])[NH:22]1
Reactant: O=C(O)c1cccc(NCc2cccs2)c1C(=O)O
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4cccs4)c3C2=O)C(=O)N1
Yield: 29 %

Procedure:
3-[(Thiophen-2-ylmethyl)-amino]-phthalic acid (2.88 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was purified by preparative HPLC (Symmetry C18, isocratic, 35% acetonitrile/water) to give 0.31 g (29%) of product as a yellow solid: mp 223–225° C.; 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.39 (d, J=4.8 Hz, 1H), 7.23–6.96 (m, 5H), 5.07 (dd, J=5.3 and 12.4 Hz, 1H), 4.75 (d, J=6.0 Hz, 2H), 2.97–2.83 (m, 1H), 2.63–2.46 (m, 2H), 2.09–1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.77, 170.03, 168.67, 167.20, 145.60, 142.51, 136.04, 132.15, 126.88, 125.40, 125.00, 117.67, 111.05, 109.80, 48.56, 40.88, 30.96, 22.10; Anal. Calcd. For C18H15N3O4S: C, 58.53; H, 4.09; N, 11.38. Found: C, 58.20; H, 3.96; N, 10.99.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([NH:11][CH2:12][C@@H:13]([OH:28])[C@@H:14]([NH:24][C:25](=[O:27])[CH3:26])[CH2:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.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>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([F:22])[CH:19]=1)[CH2:15][C@H:14]([NH:24][C:25](=[O:27])[CH3:26])[C@H:13]([OH:28])[CH2:12][NH:11][C:8]1([C:4]2[CH:3]=[C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[CH:36]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:9]1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(Br)c2)CC1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(-c2cccc(C3(NC[C@@H](O)[C@H](Cc4cc(F)cc(F)c4)NC(C)=O)CC3)c2)c1
Temperature: 90 °C
Yield: 31.4 %

Procedure:
To a solution of N-[(1S,2R)-3-{[1-(3-bromophenyl)cyclopropyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide (0.030 g) in DMF (0.75 mL) was added 3-methoxyphenylboronic acid (0.030 g), Cs2CO3 (0.085 g) and Pd(Ph3P)4. The mixture was heated for 12 h at 90° C. The cooled solution was diluted with EtOAc (15 mL) and washed with brine (10 mL×2). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by column chromatography to give 0.010 g of the title compound. ES+ found (M+H+):481.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[Cl:6]C([O:9][C:10]([Cl:13])(Cl)Cl)=O.[NH2:14][C:15]1[S:16][CH:17]=[C:18](/[C:20](=[N:24]/[O:25][CH3:26])/C(O)=O)[N:19]=1.C(OC(C)C)(=O)C>O1CCCC1>[ClH:6].[CH3:1][N:2]([CH:3]=[N:14][C:15]1[S:16][CH:17]=[C:18](/[C:20](=[N:24]/[O:25][CH3:26])/[C:10]([Cl:13])=[O:9])[N:19]=1)[CH3:5]
Reactant: CN(C)C=O
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)Cl)c1csc(N=CN(C)C)n1
Product: Cl
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Dimethylformamide (0.8 g, 11 mmol) was added to 9 of tetrahydrofuran, followed by ice-cooling. To the resulting mixture, 0.6 ml of trichloromethyl chloroformate was added dropwise under ice-cooling. After stirring the resulting mixture for 30 minutes, the mixture was cooled to -10° C. (Z)-2-(2-Amino-thiazol-4-yl)-2-methoxyiminoacetic acid (840 mg, 4.2 mmol) was added and the mixture so obtained was stirred for 2 hours. The mixture was added with 9 ml of isopropyl acetate, followed by stirring for 30 minutes. A precipitate was collected by filtration under a nitrogen gas stream and then dried at room temperature, whereby 1.23 g of the title compound were obtained (yield: 94%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)/[CH:9]=[CH:10]/[C:11]#N)=[CH:2]1.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:27]>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)/[CH:9]=[CH:10]/[CH:11]=[O:27])=[CH:2]1
Reactant: N#C/C=C/c1cccc(-c2ccsc2)c1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=C/C=C/c1cccc(-c2ccsc2)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
0.4 g of the resulting nitrile compound was dissolved in 2 ml of toluene, and under cooling at -78° C., a 1.0M toluene solution(2 ml) of diisobutylaluminum hydride was added. The mixture was stirred at this temperature for 20 minutes, and then poured into ice-cold water. The resulting solution was acidified with a small amount of a 10% aqueous solution of sulfuric acid, and extracted with ethyl ether. The extract was worked up in a customary manner, and purified by medium-pressure liquid chromatography [silica gel column, hexane/ethyl acetate=9/1→7/1] to give 0.2 g of the captioned compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([CH2:23][OH:24])[O:20][N:19]=1)=[O:17].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:24][CH2:23][C:21]1[O:20][N:19]=[C:18]([C:16](=[O:17])[NH:15][CH3:14])[CH:22]=1
Reactant: CNC(=O)c1cc(CO)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2.58 g (12.81 mmoles) of 4-nitrophenyl chloroformate are added in small portions to a solution of 2.00 g (12.81 mmoles) of 3-methylcarbamoyl-isoxazol-5-ylmethanol (commercial), 1.52 g (19.21 mmoles) of pyridine and 0.157 g (1.28 moles) of N,N-dimethylaminopyridine in 15 ml of dichloromethane, cooled to about 0° C. The medium is maintained with stirring for 1 hr at 0° C. then for 1 hr at ambient temperature. The precipitate formed is filtered off, then copiously rinsed with diisopropyl ether. After drying under vacuum at about 60° C., 2.6 g of pure product are obtained in the form of a white powder.
Reaction SMILES: [OH:1]N.C(OC(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:17]=[CH:16][N:15]=1)C.C[N:35]([CH:37]=[O:38])C>CO>[OH:1][NH:35][C:37](=[O:38])[CH:12]([N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:17]=[CH:16][N:15]=1)[CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: NO
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2C)ccn1
Solvent: CO
Product: CCCCCC(C(=O)NO)N(c1ccccn1)c1cc(-c2ccccc2C)ccn1
Reaction time: 22 h
Yield: 55 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (37 mg, 0.09 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:8) to furnish III as a yellow oil (20 mg, 55%).
Reaction SMILES: O=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1)=[O:6].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O=P(Cl)(Cl)Cl.C(OCC)(=O)C>[C:19]1([C:2]2[O:6][C:5]([C:7]3[CH:8]=[N:9][C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][CH:12]=3)=[N:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CNC(=O)c1cnc(-c2ccccc2)nc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: c1ccc(-c2ncc(-c3ncc(-c4ccccc4)o3)cn2)cc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
To a solution consisting of N-(2-oxo-2-phenylethyl)-2-phenylpyrimidine-5-carboxamide (Step A, 80 mg, 0.25 mmol) in POCl3 (1.0 mL) was added pyridine (2.0 mL). The solution was heated at 70° C. for six hours and was subsequently allowed to cool to room temperature. The solution was diluted with ethyl acetate (10 mL) and poured into a chilled saturated aqueous sodium bicarbonate solution (40 mL). After stirring for 15 minutes, the mixture was extracted with ethyl acetate (3×25 mL) and the combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography (0-5% methanol in dichloromethane gradient) through a 40-g Silicycle® flash silica cartridge to afford the title compound as an off-white solid (49 mg, 65% yield); Rf 0.80 with 2% methanol in dichloromethane; 1H-NMR (300 MHz; DMSO-d6) δ 9.52 (s, 2H), 8.48 (dd, 2H), 7.99 (s, 1H), 7.94 (dd, 2H), 7.43-7.60 (m, 6H); MS (ESI+) m/z 300 (M+1); H-PGDS FPBA IC50: >20 μM.