Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC.C[O-].[Na+]>>[OH:4][CH2:3][CH2:2][N:1]1[CH2:5][CH2:6][O:7][C:8]1=[O:9]
Reactant: OCCNCCO
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Product: O=C1OCCN1CCO

Procedure:
A mixture of diethanolamine (12.55 g), diethyl carbonate (16.2 mL), and sodium methoxide (80 mg) was heated to 130–140° C. for 1.5 h and distilled during the reaction using a Dean-Stark trap. The remaining liquid was concentrated in vacuo to give 15.11 g (97%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:29]=[CH:28][C:12]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=2)=[C:4]([C:30]#[N:31])[CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.CO>[C:30]([C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:33]([F:32])[CH:34]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[CH:29]=[CH:28][C:12]([C:13]([N: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)=[O:14])=[CH:11][CH:10]=1)#[N:31]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Nc3ccc(Br)cc3C#N)cc2)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: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(-c2ccc(Nc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c(C#N)c2)cc1F
Temperature: 105 °C
Yield: 96.1 %

Procedure:
A 125 ml pressure flask was loaded with tert-butyl 4-(4-(4-bromo-2-cyanophenylamino)benzoyl)piperazine-1-carboxylate (6.55 g, 13.49 mmol), 3-fluoro-4-methoxyphenylboronic acid (2.75 g, 16.19 mmol) and Pd(Ph3P)4 (0.43 g, 0.372 mmol). Toluene (45 mL), MeOH (22.50 mL) and a 2 molar solution of Na2CO3 (16.87 mL, 33.7 mmol) were added, the flask flushed with nitrogen, sealed and heated to 105° C. for 5 hours. The reaction mixture was poured into a separating funnel loaded with water and dichloromethane, the layers separated and the aqueous layer extracted one more time with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica. Gradient from 100% CH2Cl2 to 67% CH2Cl2+33 ethyl acetate. Product containing fractions were combined and concentrated in vacuum. 6.88 g tert-butyl 4-(4-(3-cyano-3′-fluoro-4′-methoxybiphenyl-4-ylamino)benzoyl)-piperazine-1-carboxylate were isolated as a pale yellow foam of ˜80% purity. The material was used in then next step without further purification. MS (ESI) m/z 529 (M−H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C[Al](C)C.[C:22](OCC)(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1(C)C=CC=CC=1>[C:23]1([C:22]2[N:4]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:3][CH2:2][N:1]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCN)CC1
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2CCN=C2c2ccccc2)CC1
Temperature: -10 °C

Procedure:
To tert-butyl 4-[(2-aminoethyl)amino]piperidine-1-carboxylate (6 g) taken in dry toluene (50 ml) cooled to −10° C., trimethylaluminium was added slowly in dry toluene under nitrogen atmosphere. Reaction mixture was allowed to warm to r.t. and a second lot of solution of tert-butyl 4-[(2-aminoethyl)amino]piperidine-1-carboxylate (6 g in 50 ml of toluene) was added very slowly to it. The combined mixture was heated up to 55° C. for 30 minutes. A solution of ethyl benzoate (7.4 g in 50 ml of dry toluene) was added very-very slowly to the reaction mixture at 55° C. over a period of 40 minutes. After the completion of addition, the reaction mixture was refluxed for over night. Reaction mixture was cooled to 0° C. and water (3×50 ml) was added. The combined mixture was filtered through celite pad. The filtrate was concentrated under reduced pressure and the resulting oil was purified by column chromatography to afford tert-butyl 4-(2-phenyl-4,5-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate as a pure product.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]([CH2:11]OS(C)(=O)=O)([CH2:9][OH:10])[CH2:7][N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:5]1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]1[C:8]([CH2:11][N:24]=[N+:25]=[N-:26])([CH2:9][OH:10])[CH2:7][N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: CON=C1CN(Cc2ccccc2)CC1(CO)COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=C1CN(Cc2ccccc2)CC1(CO)CN=[N+]=[N-]
Temperature: 110 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
1-benzyl-4-methanesulfonyloxymethyl-4-hydroxymethyl-pyrrolidine-3-one-O-methyloxime was dissolved in 400 ml of dimethylformamide and thereto 21 g of sodium azide was added and the resulting solution was stirred for 6 hours at 110° C. The reaction mixture was concentrated under the reduce pressure, diluted with 300 ml of ethylether, washed twice with each 200 ml of water and twice with each 200 ml of saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure to give 31 g of 1-benzyl-4-azidomethyl-4-hydroxymethyl-pyrrolidine-3-one-O-methyloxime (yield: 87.3%). The obtained compound and 18 ml of triethylamine were added into 300 ml of dichloromethane and cooled to 0-5° C., and thereto 9.0 ml of methanesulfonylchloride was slowly added by dropping. The reaction temperature was increased up to room temperature and the mixture was stirred for 1 hour. The reaction mixture was washed with 200 ml of water and 200 ml of saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure and the concentrated residue was purified by silicagel column chromatography(ethylacetate:normal hexane=1:3) to give 38.8 g of the titled compound (yield: 98.4%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[CH3:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1B(O)O>>[CH2:28]([C:11]1[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:32]2[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=2[CH3:30])[N:10]=1)[CH3:29]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1ccc(B(O)O)c(C)c1
Product: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 2-methyl-4-methoxyphenylboronic acid and making non-critical variations provided the title compound as a peach colored foam. IR (diffuse reflectance) 3439, 2968, 2933, 2875, 1608, 1564, 1482, 1391, 1294, 1279, 1242, 1204, 1175, 1050, 742 cm−1; OAMS supporting ions at: ESI+ 404.0 & ESI− 402.1; MS (EI) m/z 403 (M+); HRMS (FAB) calcd for C25H29N3O2+H1 404.2338, found 404.2324. Anal. Calcd for C25H29N3O2: C, 74.41; H, 7.24; N, 10.41. Found: C, 74.05; H, 7.44; N, 10.28.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:32]([NH:34][CH3:35])=[O:33])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][OH:45]>C(#N)C.CCOC(C)=O>[CH:1]1([C:4]2[C:12]([N:13]([CH2:43][CH2:44][OH:45])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:32]([NH:34][CH3:35])=[O:33])[N:8]([C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: OCCBr
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
To a solution of Compound (2) (13 mg, 26 μmol) in ACN (1 mL) was added potassium carbonate (7.3 mg, 52 μmol) followed by 2-bromoethanol (5.6 μL, 79 μmol). The mixture was then stirred at 80° C. for 16 h (monitored by LCMS). The mixture was cooled to RT, diluted with EtOAc (3 mL), washed with water (1 mL) and brine (2 mL). The organic phase was dried (MgSO4) and the solvent was removed in vacuo. The crude mixture was purified by preparative HPLC to give Compound (3) (4.86 mg, 34%) as a white powder. ESI-MS m/z calculated for [M+H]+: 539.18; found: 539.12; 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.52 (brd, J=9.0 Hz, 2H), 7.47 (s, 1H), 7.12-7.02 (m, 6H), 5.79 (brd, J=4.3 Hz, 1H), 4.21-4.00 (m, 1H), 3.85-3.62 (m, 3H), 3.18 (s, 3H), 2.99 (d, J=4.9 Hz, 3H), 2.51-2.27 (m, 1H), 1.06 (ddd, J=11.3, 6.9, 3.1 Hz, 3H), 0.62-0.44 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[F:32]C1C=CC(CCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:32][C:7]1[CH:6]=[CH:5][C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:3][CH:2]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2ccc(F)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-fluoro-phenyl)-propanoic-acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]([OH:16])=O)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:58]1[C:66]2[C:61](=[C:62]([CH2:67][NH2:68])[CH:63]=[CH:64][CH:65]=2)[CH:60]=[N:59]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:16])[NH:68][CH2:67][C:62]2[CH:63]=[CH:64][CH:65]=[C:66]3[C:61]=2[CH:60]=[N:59][NH:58]3)=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C(F)(F)F
Reactant: NCc1cccc2[nH]ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.1 %

Procedure:
To a solution of 3-Trifluoromethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (630 mg, 2.47 mmol) in anhydrous DMF (12 mL) was added triethylamine (1.03 mL, 7.41 mmol), HBTU (1.41 g, 3.71 mmol), HOBT (0.40 mg, 2.96 mmol), and C-(1H-Indazol-4-yl)-methylamine (400 mg, 2.72 mmol). The mixture was stirred at room temperature 5 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-80% EtOAc in hexane to afford the desired product (0.20 g, 21% yield).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:18])[C:7]=2[CH:6]=[CH:5][C:4]=1[F:21].Cl.[NH2:23][OH:24]>CO>[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17](=[N:23][OH:24])[NH2:18])[C:7]=2[CH:6]=[CH:5][C:4]=1[F:21]
Reactant: CN1Cc2c(C#N)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN1Cc2c(C(N)=NO)ncn2-c2ccc(F)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 67 h
Yield: 83.3 %

Procedure:
1.0 g (0.0432 mol) of sodium was dissolved in 60 ml of methanol. 8.85 g (0.0304 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile and 3.25 g (0.0469 mol) of hydroxylamine hydrochloride were added thereto in succession at room temperature. The white suspension was stirred at room temperature for 67 hrs. and evaporated, whereupon the residue was suspended in 100 ml of water and the crystals were filtered off. By drying the crystallizate there were obtained 8.2 g (83%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime as white crystals; m.p. 228°-231°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 69 %

Procedure:
By the reaction of ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate with 4-chlorobenzenesulphonyl chloride in a manner analogous to that described in Example 2, there is obtained, in a yield of 69% of theory, colorless ethyl 2-{4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-phenoxy}-2-methylpropionate in the form of a viscous oil. From this there is obtained, by hydrolysis:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([C@@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)[CH2:33][C:34]#[CH:35].CN(C=O)C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:35]#[C:34][CH2:33][CH2:32][C@@H:36]4[CH2:40][O:39][C:38](=[O:41])[NH:37]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCC[C@@H]1COC(=O)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCC[C@@H]3COC(=O)N3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added (4R)-4-(3-butynyl)-1,3-oxazolidin-2-one (83.4 mg). Anhydrous DMF (20 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), and 2.5% MeOH in CH2Cl2 (3L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 95.6 mg (31%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@:11]([CH3:15])([OH:14])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:18](OC)([CH3:20])[CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][C@@:11]1([CH3:15])[CH2:12][O:13][C:18]([CH3:20])([CH3:19])[O:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: C[C@@](O)(CO)CCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OC[C@](C)(CCOCc2ccccc2)O1

Procedure:
To the mixture of compound 2 and 2,2-dimethoxypropane in DCM was added p-TSA. After TLC monitoring showed the disappearance of the starting material, aqueous NaHCO3 solution was added and then extracted with ethyl acetate three times. The combined organic phase was washed with brine and dried (Na2SO4). The solid was filtered and the solvent was removed. The residue was purified by column chromatography to give compound 3.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.Cl.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[C:36]([O:38][CH2:39][CH3:40])=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH:28]3[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:25])[CH:18]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: CCOC(=O)C1Cc2ccccc2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
150 mg (0.44 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]pyrimidine-4-carboxylic acid, 110 mg (0.48 mmol) ethyl 2,3-dihydro-1H-indole-2-carboxylate hydrochloride, 150.0 mg (0.47 mmol) TBTU and 150 μL (1.1 mmol) triethylamine in 2 mL DMF were stirred overnight at RT. The mixture was filtered through a syringe filter and the solution was purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[CH2:12][C:13]#[N:14].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O.O>[F:11][C:4]1[C:3]([CH2:12][C:13]#[N:14])=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: N#CCc1c(F)ccc([N+](=O)[O-])c1F
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Yield: 17.6 %

Procedure:
A solution of (2,6-difluoro-3-nitrophenyl)acetonitrile (4 g, 20.1 mmol) and aniline (1.83 mL, 20.1 mmol) in DMSO (20 mL) was heated at 100° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as brown oil (959 mg, 18%). 1H NMR 400 MHz 6 (CDCl3): 8.27 (1H, dd, J=9.4, 5.9 Hz), 7.38-7.32 (2H, m), 7.17-7.12 (1H, m), 6.98-6.90 (3H, m), 3.44 (2H, d, J=1.7 Hz).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:16]=[C:15]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:14]=1)[C:3]([OH:25])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2cccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Chill a solution of N-methyl-N-propyl-5-(pyridine-3-carbonyl)-isophthalamic acid methyl ester (0.070 g, 0.206 mmol) in MeOH (1 mL) and THF (1 mL) in an ice bath. Add 1 N NaOH (0.62 mL, 0.62 mmol) and stir at room temperature for 2 h. Acidify the solution to about pH=2 and concentrate to one half of the solvent. Partition the residue between ethyl acetate and H2O. Extract the aqueous layer with ethyl acetate (2×15 mL). Wash the combined organic extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (72%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([CH2:25][N:26]([CH:42]([CH3:44])[CH3:43])[C:27](=[O:41])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C@H:22]([CH2:45]O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([CH2:25][N:26]([CH:42]([CH3:44])[CH3:43])[C:27](=[O:41])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C@H:22]([CH2:45][N:51]2[C:47](=[O:57])[C:48]3[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:50]2=[O:52])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN2C(=O)c3ccccc3C2=O)C(C)C)ccc1C

Procedure:
DEAD is slowly added to a solution of (3S,4R)-3-hydroxymethyl-4-({isopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (210 mg, 0.44 mmol), phthalimide (07 mg, 0.66 mmol) and PPh3 (173 mg, 0.66 mmol) in THF (5 mL) at RT. The resulting yellow solution is stirred for another 2 h before H2O is added and the mixture is extracted with ethyl acetate. Drying (Na2SO4) of the extracts, filtration and evaporation of the solvent affords the crude product which is purified by preparative HPLC (Waters C18 ODB, eluent: CH3CN/H2O 5%/2 min, CH3CN/H2O 5-100%/10 min, 100% CH3CN/2.5 min, flow 20 mL/min) to give the desired product. MS (LC-MS): 630.2 [M+Na]+; tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.40 min.