Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[C:30](=[O:31])[N:6]2[CH:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])([OH:11])[CH2:9][S:10][C@:5]12[S:32][CH3:33])=[N+:2]=[N-:3].CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[N:1]([CH:4]1[C:30](=[O:31])[N:6]2[CH:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])([O:11][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:9][S:10][C@:5]12[S:32][CH3:33])=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)Cl
Reactant: CS[C@]12SCC(O)(COC(C)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS[C@]12SCC(COC(C)=O)(OS(C)(=O)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Temperature: 0 °C
Yield: 68.3 %

Procedure:
To an ice-cold, stirring solution of p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-3-hydroxy-cepham-4-carboxylate (2.72 g., 5.47 mMol) and Et3N (1.15 ml., 8.25 mMol) in anhydrous CH2Cl2 (20 ml.) is added dropwise a solution of methanesulfonyl chloride (0.51 ml., 6.56 mMol) in anhydrous CH2Cl2 (15 ml.). After stirring 15 more mins. in the cold, the solution is washed with H2O, 5% HCl, 5% NaHCO3, and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residual oil is crystallized from CH2Cl2 --MeOh to afford p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-3-methylsulfonyloxycepham-4-carboxylate (2.15 g.) as yellow crystals: mp 147° C.; ir (CHCl3) 4.72, 5.59, 5.71, 6.58 and 7.42μ; nmr (CDCl3)δ 2.17 (s, 3, COCH3), 2.20 (s, 3, SCH3), 3.00 (s, 3, SO2CH3), 3.22, 4.28 (ABq, 2, J=14Hz, SCH2, 4.67, 4.95 (ABq, 2, J=13Hz, CH2OAc), 4.88 (s, 1, H7), 5.20 (s, 1, H4), 5.35 (s, 2, CH2Ar), and 7.63, 8.25 (ABq, 4, J=9, ArH).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([C:13]2[O:17][N:16]=[C:15]([CH2:18]OS(C)(=O)=O)[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[NH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:47])[C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[C:43]([F:46])([F:45])[F:44])[CH2:31][CH2:30]1)=[O:28].O>CN(C=O)C>[F:42][C:40]1[CH:39]=[CH:38][C:37]([C:43]([F:45])([F:44])[F:46])=[C:36]([CH:41]=1)[C:35]([N:32]1[CH2:33][CH2:34][N:29]([C:27](=[O:28])[CH2:26][NH:25][CH2:18][C:15]2[CH:14]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:17][N:16]=2)[CH2:30][CH2:31]1)=[O:47]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: CS(=O)(=O)OCc1cc(-c2ccccc2)on1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNCc1cc(-c2ccccc2)on1)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Temperature: 40 °C
Yield: 18 %

Procedure:
K2CO3 (121 mg, 0.87 mmol) was added to a stirred solution of methanesulfonic acid 5-phenyl-isoxazol-3-ylmethyl ester (120 mg, 0.43 mmol) and 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (162 mg, 0.43 mmol) in DMF (2 mL). The resulting mixture was heated at 40° C. for 1 hr. Cold water was then added and the resulting precipitate was isolated by filtration. The crude solid was purified by preparative HPLC [(Column-AV/SP/C18-25/003, mobile phase-0.1% TFA in water (A)/acetonitrile (B), flow: 6 mL/min, gradient: (Time): (% B)-0:20; 2:20; 10:70)]) to afford 38 mg (17.64% yield) of 1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-[(5-phenyl-isoxazol-3-ylmethyl)-amino]-ethanone. LCMS Purity: 91.95%. 1H NMR (CDCl3): δ 7.94-7.64 (m, 3H), 7.56-7.4 (m, 3H), 7.2 (m, 1H), 7.3 (d, 1H), 6.64-6.48 (d, 1H), 4.0-3.9 (d, 2H), 3.9-3.8 (m, 1H), 3.76-3.56 (m, 2H), 3.56-3.4 (m, 4H), 3.56-3.26 (bs, 1H), 3.2 (d, 2H), 2.49-2.29 (bs, 1H).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][N:5]([CH:8]([C:11]2[CH:12]=[N:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:9][NH2:10])[CH2:4][CH2:3]1.[Cl:19][C:20]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:19][C:20]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:10][CH2:9][CH:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:18])[CH2:3][CH2:4]1)[C:11]1[CH:12]=[N:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:23]
Reactant: NCC(c1ccc(F)nc1)N1CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(c1ccc(F)nc1)N1CCC(F)(F)CC1)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
A mixture of 2-(4,4-difluoro-piperidin-1-yl)-2-(6-fluoro-pyridin-3-yl)-ethylamine (100 mg, 0.38 mmol), 2,3-dichlorobenzoic acid (51 mg, 0.28 mmol), HOBT (57 mg, 0.42 mmol), EDC.HCl (81 mg, 0.42 mmol) and DIPEA (108 mg, 0.84 mmol) in DMF (4 mL) was stirred at room temperature overnight. The mixture was purified by preparative HPLC directly to yield the title compound (43 mg, yield: 30%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1I)[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([NH:36][C:37](=[CH2:42])[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:33]([NH:36][C:37](=[CH:42][C:25]1[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:24]=1[O:23][CH2:22][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)COc1cc(C#N)ccc1I
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)NC(C)=O

Procedure:
5.72 g (10.4 mmol) of benzyl (4R)-4-t-butoxycarbonylamino-5-(5-cyano-2-iodophenoxy)pentanoate was stirred together with 3.0 g (21 mmol) of methyl 2-acetamidoacrylate, 2.0 g (6.6 mmol) of tris(2-methylphenyl)phosphine, 270 mg (1.1 mmol) of palladium (II) acetate and 3.54 g (35 mmol) of triethylamine in 50 ml of DMF at 100° C. for 5 hours. The solvent was evaporated, and the residue was treated with ethyl acetate as the extracting solvent by an ordinary method and then purified by the silica gel chromatography (ethyl acetate/hexane) to obtain the title compound.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[S:25][C:26]1[S:30][N:29]=[N:28][C:27]=1[CH3:31])[C@H:20]([NH:32][C:33](=[O:63])[C:34]([C:56]1[N:57]=[C:58]([NH2:62])[S:59][C:60]=1[Cl:61])=[N:35][O:36]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]2=[O:64])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:62][C:58]1[S:59][C:60]([Cl:61])=[C:56]([C:34](=[N:35][OH:36])[C:33]([NH:32][C@@H:20]2[C:19](=[O:64])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([S:25][C:26]2[S:30][N:29]=[N:28][C:27]=2[CH3:31])=[C:17]3[C:15]([OH:16])=[O:14])=[O:63])[N:57]=1
Reactant: Cc1nnsc1SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(c3ccccc3)(c3ccccc3)c3ccccc3)c3nc(N)sc3Cl)C2SC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnsc1SC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3nc(N)sc3Cl)C2SC1

Procedure:
To a solution of (7R)-7-[2-(2-amino-5-chlorothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(4-methyl-[1,2,3]thiadiazol-5-ylsulfanyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene 2-carboxylic acid benzhydryl ester (990 mg, 1.05 mmol) in dichloromethane (21 mL) was added triethylsilane (11 mL) followed by addition of trifluoroacetic acid (21 mL). After 1 hr at room temperature the reaction mixture was concentrated under vacuum. Disopropyl ether was added to the oily residue. The title compound precipitated and was filtered, washed with additional diisopropyl ether and dried under vacuum (528 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:14][CH3:15])=[N:4][CH:5]=[C:6]([N+:11]([O-])=O)[C:7]=1[CH2:8][CH2:9][OH:10]>C(O)(=O)C.O.[Fe]>[NH2:11][C:6]1[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([Cl:1])[C:3]([S:14][CH3:15])=[N:4][CH:5]=1
Reactant: CSc1ncc([N+](=O)[O-])c(CCO)c1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CSc1ncc(N)c(CCO)c1Cl
Reaction time: 0.5 h

Procedure:
3-Chloro-4-(2-hydroxyethyl)-2-methylthio-5-nitropyridine (0.430 g, 1.73 mmol) was dissolved in a mixture of glacial acetic acid (30 ml) and water (15 ml), and was treated with iron powder (3.78 g, 0.068 mol) with stirring. After 0.5 h, the mixture was filtered through kieselguhr and the resultant yellow solution was evaporated under reduced pressure. The residue was partitioned between sodium bicarbonate solution and ethyl acetate. The biphasic suspension was filtered through kieselguhr, and the organic layer was dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a yellow solid, which was dried in vacuo (0.275 g, 73%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])=[N:7][C:2]([C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (34 mg, 0.12 mmol) and 4-(4-BOC-piperazino)phenylboronic acid (46 mg, 0.15 mmol), the residue was purified via prep HPLC (2-95% acetonitrile in water, 0.1% trifluoroacteic acid buffer) followed by neutralization to isolate tert-butyl 4-(4-(3-methyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)piperazine-1-carboxylate 3B.15.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:15]=[C:14]([CH3:16])[S:13][CH:12]=1)[OH:4].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:15]=[C:14]([CH3:16])[S:13][CH:12]=2)[C:2]([F:1])([F:17])[F:18])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: Cc1cc(-c2ccccc2C(O)C(F)(F)F)cs1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cs1
Temperature: 110 °C
Yield: 68.2 %

Procedure:
A mixture of 2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethanol (100 mg, 0.37 mmol), 2-amino-4,6-dichloro-pyrimidine (54 mg, 0.33 mmol), cesium carbonate (481 mg, 1.48 mmol) and 1,4-dioxane (2 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 90 mg of 4-chloro-6-{2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine, yield: 68%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1C=CC=CC=1>[CH:12]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:23]=3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:14])[CH3:13]
Reactant: CC(C)c1cc(Br)c2ncccc2c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: CC(C)c1cc(-c2cccc([N+](=O)[O-])c2)c2ncccc2c1
Yield: 89.3 %

Procedure:
8-Bromo-6-isopropylquinoline (1.15 g) was dissolved in 46 mL of ethanol/benzene (1:1). 3-Nitrobenzene boronic acid (1.4 g), Na2CO3 (2M, 9.2 mL) and tetrakistriphenylphosphine palladium (0.23 g) were added successively. The reaction mixture was refluxed for 6 hours and then cooled and concentrated. The resulting residue was partitioned between 75 mL H2O and 100 mL of ethyl acetate, and extracted with ethyl acetate (2×100 mL). The extracts were then dried over MgSO4, filtered, concentrated and chromatographed on silica gel (20:80 ethyl acetate:hexane) yielding 1.2 g of 6-isopropyl-8-(3-nitrophenyl)quinoline as a slightly impure yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[CH2:14]1[C@@H:17](C(O)=O)[NH:16][CH2:15]1>CS(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[N:16]3[CH2:17][CH2:14][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2CC[C@@H]12

Procedure:
11.3 g (0.057 mol) of 6-chloro-isatoic acid anhydride and 5.78 g (0.057 mol) of L-azetidine-2-carboxylic acid are heated to 125° in 50 ml of dimethyl sulphoxide for 2 hours. The mixture is subsequently evaporated to dryness in a high vacuum and the residue obtained is heated to 150° for 2 hours. By chromatography on silica gel while eluting with ethyl acetate there is obtained (S)-5-chloro-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione of melting point 225°-228°.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].[Cl:6][C:7]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:8]=1[CH:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12]>>[NH2:14][CH2:13][C:10]1[C:11]([NH2:12])=[N:5][C:3]([S:2][CH3:1])=[N:4][C:9]=1[C:8]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:7]=1[Cl:6]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: CSC(=N)N
Product: CSc1nc(N)c(CN)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
The title compound, MS: m/e=315.2 (M+), was prepared from 2-methyl-isothiourea and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:20][NH:21][CH2:22][CH:23]2[CH2:28][O:27]C(C)(C)[O:25][CH:24]2[CH2:31][S:32][CH3:33])=[CH:11]1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.O.O.NN>[Pd]>[NH2:19][C:17]1[C:18]2[NH:10][CH:11]=[C:12]([CH2:20][NH:21][CH2:22][CH:23]([CH:24]([OH:25])[CH2:31][S:32][CH3:33])[CH2:28][OH:27])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CSCC1OC(C)(C)OCC1CNCc1cn(COCc2ccccc2)c2c(N)ncnc12
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CSCC(O)C(CO)CNCc1c[nH]c2c(N)ncnc12
Yield: 62.4 %

Procedure:
The product of Example 9.3 (17 mg, 0.036 mmol) was treated with TFA/water (9:1 v/v, 1 mL). After 5 min the mixture was evaporated in vacuo. The residue was redissolved in methanolic ammonia (7M, 4 mL) and Pd-black (17 mg, 0.16 mmol) was added, followed by hydrazine hydrate (250 μL, 5.1 mmol). After 15 min more Pd-black (22 mg, 0.21 mmol) was added and again after further 15 min (55 mg, 0.52 mmol) and also hydrazine hydrate (0.5 mL, 10.2 mmol). Shortly after the mixture was filtered through flux calcined diatomaceous earth and evaporated. The residue was dissolved in MeOH (2 mL) and treated with Amberlyst® A-26(OH) ion exchange resin (˜1 g) for 5 min, the solution was filtered and evaporated in vacuo which gave the product as an oil (7 mg, 62%). 1H NMR (CD3OD) δ 8.16 (s, 1H), 7.48 (s, 1H), 3.97-3.80 (m, 2H), 3.79-3.61 (m, 2H), 3.16-3.05 (m, 1H), 2.85 (dd, J=6.0, 12.1, 1H), 2.79 (dd, J=6.7, 12.0 Hz, 1H), 2.66 (dd, J=4.8, 13.5 Hz, 1H), 2.56 (dd, J=8.0, 13.5 Hz, 1H), 2.11-1.88 (m, 4H). 13C NMR (CD3OD, referenced to the middle methanol peak at 49.0 ppm) δ 150.8, 146.5, 129.1, 114.6, 72.1, 62.1, 45.5, 43.9, 40.1, 16.3. HRMS: (M+H)+ calcd. for C13H22N5O2S: 312.1494. found: 312.1494.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[C:28]([N:15]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][C:17]([F:18])([F:20])[F:19])=[O:29])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1ncccc1-c1ccncc1NCC(F)(F)F
Product: COc1ncccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2-methoxy-[3,4′]bipyridinyl-3′-yl)-(2,2,2-trifluoro-ethyl)-amine (example 135, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of CH2Cl2: EtOAc (100:0 to 85:15), followed by preparative HPLC using a gradient of methanol:water (10:50 to 95:5). Light yellow foam (28%). MS (ESI): m/z=534.090 [M+H]+.
Reaction SMILES: [CH:1]([CH:4]1[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2].[CH2:9](O)CO>[Pd]>[CH2:4]([O:5][CH:6]([CH3:9])[CH2:7][OH:8])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)C1OCCO1
Reactant: OCCO
Agent: [Pd]
Product: CC(C)COC(C)CO
Temperature: 200 °C
Reaction time: 2 h

Procedure:
20 g of 2-isopropyl-1,3-dioxolane and 100 g of ethylene glycol were combined in a 300 mL stainless steel autoclave. 2.0 g of 5% Pd/C catalyst were added and the autoclave was sealed. The reactor was heated to 200° C. The reactor was then brought to an operating pressure of 3.45 MPa and stirring commenced at 750 rpm. Pressure was maintained through the duration of the experiment. After 2 h, the autoclave was cooled and remaining gas vented. The autoclave was opened, its contents filtered, and the filtrate analyzed by gas chromatography (GC). 83% conversion of the acetal mixture was observed. Upon analysis of the results, the mixture was found to demonstrate 95.8% selectivity to 2-isobutoxy-ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of the product of Example 57a (553 mg, 1.557 mmol) in anhydrous DMF (15 mL) was treated with 4-mercaptophenol (196 mg, 1.557 mmol) and cesium carbonate (1.015 g, 3.114 mmol) at room temperature, then heated at 100° under a nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature and the solvent concentrated under vacuum giving the title compound. The residue was taken up in H2O (30 mL) and the pH adjusted to 3 with 1N aqueous HCl. The aqueous was then extracted with ethyl acetate, and the combined organic extracts washed with brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum giving the title compound. The residue was triturated with methylene chloride and purified by silica gel flash chromatography with a gradient of 6% to 30% ethyl acetate/methylene chloride to afford the title product as a dark yellow solid (517 mg, 1.16 mmol, 75%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[C:13]1[CH:14]=[CH:15][C:16]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:17]([CH:20]=1)[C:18]#[N:19]>CS(C)=O.[Pd]>[C:18]([C:17]1[CH:20]=[C:13]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:14]=[CH:15][C:16]=1[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])#[N:19]
Reactant: CC(C)COc1ccc(Br)cc1C#N
Reactant: CCOC(=O)c1scnc1C
Agent: [Pd]
Solvent: CS(C)=O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 120 °C

Procedure:
To a test tube-type reaction vessel (10 mL) were added ethyl 4-methylthiazole-5-carboxylate (85.5 mg, 0.5 mmol), 5-bromo-2-isobutoxybenzonitrile (127.1 mg, 0.5 mmol) obtained in Reference Example 3, a palladium species, a ligand, a base (1.0 mmol), an additive (0.15 mmol), and a solvent (1.7 mL). Thereafter, the reaction vessel was filled with nitrogen, heated to 120° C. under airtight seal, and the reaction mixture was stirred. After the reaction was complete, a portion of the reaction mixture was diluted with DMSO and the solution obtained was measured by HPLC. The total HPLC area % of the compounds A to D and TM was set as 100% and the calculated yield of the target material was computed from the HPLC area % of the target material. The results are shown in Table 10.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C(O)(=O)C.CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C=NNC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of 4-hydroxybenzhydrazide (0.3 g, 0.002 mol) and p-anisaldehyde (0.27 g, 0.002 mol) in abs. EtOH (10 mL) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.51 g, in 93% yield, mp: 209.0° C. 1H NMR (CD3OD) δ 8.23 (s, 1H), 7.82 (d, 2H), 7.76 (d, 2H), 6.97 (d,2H), 6.87 (d, 2H), 3.82 (s, 3H). 13C NMR (CD3OD) δ 166.8, 163.2, 162.7, 149.8, 130.8, 130.4, 128.2, 124.8, 116.3, 115.2, 55.9. Anal. Calcd for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found: C, 66.82; H, 5.28; N, 10.38.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:41][CH2:42][CH2:43][F:44]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:41][CH2:42][CH2:43][F:44])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: FCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 93 mg (0.20 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate (Example 1b) in 9 mL N,N-dimethylformamide were added 60.7 mg (0.44 mmol) of powdered potassium carbonate and 45 mg (0.24 mmol) of 1-iodo-3-fluoropropane (ABCR GmbH, Germany) and the resulting suspension was stirred for 5 h at 60° C. and overnight at room temperature. The reaction mixture was than filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product obtained in this manner was chromatographed on silica gel using a dichloromethane/methanol gradient, and the appropriate fractions were combined and concentrated.