Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=S)[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].NNC(N)=S>C(O)C>[CH3:21][C:19]1[NH:10][N:9]=[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NNC(=S)Nc1ccccc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: NNC(N)=S
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccccc2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 16.7 g (0.1 mole) of 4-phenyl-3-thiosemicarbazide in 60 mL of absolute ethanol was treated with 16.5 g (0.1 mole) of ethyl 2-chloroacetoacetate and the mixture stirred for 1 hr at room temperature. As the thiosemicarbazide began to dissolve the reaction mixture became exothermic and a reddish-brown solid precipitated. Alcoholic hydrogen chloride (2N, 50 mL) was added, and the reaction mixture heated at reflux for 1.0 hr. The solution was filtered while hot and the filtrate was evaporated under reduced pressure. The solid residue was triturated in cold absolute ethanol and a red solid collected by filtration. The solid was warmed in 2N hydrochloric acid (100 mL) and the suspended sulfur removed by filtration. An orange-red solid precipitated from the filtrate, was collected by filtration and air dried for ~16 hr (14.6 g, mp 160°-40° C.). Recrystallization from benzene left 10.5 g of product, mp 165°-6° C. The material was air dried and submitted for elemental analysis.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][CH:13]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:14]([OH:16])=[O:15].[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH2:22]([O:20][C:19]([CH2:18][CH2:17][CH:13]([CH2:12][S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:14]([OH:16])=[O:15])=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)CCC(CSc1ccc2ccccc2c1)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: O=C(CCC(CSc1ccc2ccccc2c1)C(=O)O)OCc1ccccc1

Procedure:
To a solution of 2-(2-naphthylthiomethyl)glutaric acid (14.0 g) in acetonitrile (180 ml) was added benzyl alcohol (57 ml) followed by p-toluenesulfonic acid (0.52 g), and the mixture was refluxed for 23 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica eluting with dichloromethane/methanol (70:1), and recrystallized from ethyl acetate-hexane to give 11.0 g of 2-(2-benzyloxycarbonylethyl)-3-(2-naphthylthio)propionic acid.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([S:14]([NH:1][C@@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C(O)[C@H](CO)NS(=O)(=O)c1ccccc1

Procedure:
In analogy to example 2, L-serine was reacted with benzenesulfonyl chloride to give (S)-2-benzenesulfonylamino-3-hydroxy-propionic acid.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:27][C:28]([F:35])([F:34])[C:29]1[CH:33]=[CH:32][NH:31][N:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CCOC(C)=O.[Cu]I>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([N:31]3[CH:32]=[CH:33][C:29]([C:28]([F:35])([F:34])[F:27])=[N:30]3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-n3ccc(C(F)(F)F)n3)cc2)C(=O)O1
Temperature: 130 °C
Yield: 42.7 %

Procedure:
(R)-6-Allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (20 mg, 0.048 mmol), 3-(trifluoromethyl)-1H-pyrazole (20 mg, 3 equiv.), CuI (1.4 mg, 15% mol), (1R,2R)-(−)-1,2-transcyclohexanediamine (2 mg, 30% mol), K3PO4 (20 mg, 2 equiv.) were mixed with dry toluene (2 mL) and heated in Microwave Oven for 1 h at 130° C. LC-MS found product peak. The mixture was diluted with EtOAc (8 mL), washed by water (2 mL), brine (3 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified chromatography on a 4-g silica gel cartridge eluted with a gradient from 5 to 55% EtOAc in gexanes to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one (9.7 mg, 43%) product. LC-MS Method 1 tR=2.05, min, m/z=474; 1H NMR (CDCl3) 7.86 (s, 1H), 7.43 (d, 2H), 7.26 (t, 2H), 7.01 (dd, 2H), 6.69 (d, 1H), 5.76-5.64 (m, 2H), 5.05 (dd, 2H), 2.95 (m, 1H), 2.65-2.51 (m, 2H), 1.54 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1cccc(C(F)(F)F)c1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 3-trifluoromethyl-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.47 (br s, 1H), 8.12 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.74 (s, 1H), 7.57-7.69 (m, 4H), 4.67 (s, 2H). [M+H] calc'd for C14H11F3N2O2, 297; found 297.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[CH2:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O.CN>CN(C=O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[CH2:18][NH2:19])[CH:8]=[CH:7]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(CBr)c1
Agent: CN
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCc1cccc(Cn2ccc3cc(F)ccc32)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 110.5 %

Procedure:
Sodium hydride (55% dispersion in oil, 63 mg, 1.44 mmol) was added to a solution of 5-fluoro-indol (150 mg, 1.11 mmol) in dry DMF (3 mL). The mixture was stirred under nitrogen for 15 min. 2-(3-Bromomethyl-benzyl)-isoindole-1,3-dione (403 mg, 1.22 mmol) was added and the mixture was stirred at room temperature over night. After cooling, aqueous methylamine (40%, 5 mL) was added and this mixture was heated at 80° C. over night. Ethyl acetate was added and the organic phase was washed three times with water, brine, dried and concentrated to give 312 mg of the sub-title compound sufficiently pure for the next step.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][OH:17])=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:36])=[CH:27][C@H:28]1[C@H:30]([C:31](Cl)=[O:32])[C:29]1([CH3:35])[CH3:34].O>C(OCC)C>[F:25][C:26]([F:36])=[CH:27][C@H:28]1[C@H:30]([C:31]([O:17][CH2:16][C:4]2[C:5]3[CH2:11][CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[C:6]=3[CH:1]=[CH:2][CH:3]=2)=[O:32])[C:29]1([CH3:34])[CH3:35]
Reactant: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)Cl
Reactant: OCc1cccc2c1CCCc1ccccc1-2
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)OCc1cccc2c1CCCc1ccccc1-2

Procedure:
To a stirred solution of 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-methanol (0.95 g, 0.043 mole) and 1 ml of dry triethylamine in 15 ml of dry diethyl ether was added 3 ml of a solution of trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in dry diethyl ether (1.42 mmole/ml). The resultant mixture was stirred at room temperature for approximately 18 hours, then poured into 50 ml of water. The organic phase was separated and washed first with an aqueous 5% sodium bicarbonate solution and then with water. The organic solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave an oil. This oil was purified by column chromatography on silica gel, eluted with ethyl acetate:hexanes (5:95), to yield 0.83 g of (6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-yl)methyl trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylate as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:24][C:25]([F:28])([F:27])[F:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:22])([CH3:21])[CH2:13][C:14](=[O:20])[N:15]3[CH2:18][CH3:19])=[CH:10][C:9]=2[CH3:23])[CH:7]=1.[C:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[C:30]([CH3:32])=[CH2:31]>>[C:35]([O:34][C:29](=[O:33])[C:30]([CH3:32])=[CH:31][C:2]1[CH:3]=[CH:4][C:5]([O:24][C:25]([F:28])([F:26])[F:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:22])([CH3:21])[CH2:13][C:14](=[O:20])[N:15]3[CH2:18][CH3:19])=[CH:10][C:9]=2[CH3:23])[CH:7]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(Br)ccc3OC(F)(F)F)cc21
Reactant: C=C(C)C(=O)OC(C)(C)C
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=C(C)C(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21

Procedure:
Compound 9C was prepared form Compound 9B using a procedure similar to that described for Example 5C, except that t-butyl methacrylate was used as the coupling reagent. MS (electrospray): mass calculated for C26H28F3NO4, 475.20; m/z found, 476.2[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:13]([O:15]C)=O.[CH:17]([NH2:19])=O>>[CH3:12][O:11][C:7]1[C:6]2[C:2]3[N:1]=[CH:17][NH:19][C:13](=[O:15])[C:3]=3[S:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1sc2cccc(OC)c2c1N
Reactant: NC=O
Product: COc1cccc2sc3c(=O)[nH]cnc3c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
A mixture of methyl 3-amino-4-methoxybenzothiophene-2-carboxylate (202 mg, 0.85 mmol) and formamide (2 mL) is heated at 135 C. for 1 hr and the temperature is raised to 190 C. After 8 hr the reaction is cooled to r.t. Upon-cooling, black solid forms and is collected by filtration. The precipitate is air dried to give 9-methoxy-4-oxo-3H-benzothieno[3,2-d]pyrimidine (45 mg, 22.5%). 1H NMR (DMSO) δ12.0 (1H, brs), 8.31 (1H, s)7.70-7.55 (2H, m), 7.10 (1H, d, J=7.7 Hz), 3.97 (3H, s).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1)=[CH2:2]>CO>[CH2:1]([C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc(C(=O)OC)o1
Solvent: CO
Product: CCc1ccc(C(=O)OC)o1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of methyl 5-ethenyl-2-furancarboxylate (1.3 g, 8.54 mmol) in methanol (15 ml) was added PdOH2 (0.240 g, 1.71 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N2, filtered through Celite and concentrated affording methyl 5-ethyl-2-furancarboxylate (1.2 g, 7.16 mmol, 84% yield) as a clear oil which was used without further purification: LCMS (ES) m/e 155 (M+H)+.
Reaction SMILES: C(#N)C[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl.[C:16]([OH:19])(=[O:18])[CH3:17]>>[C:16]([OH:19])(=[O:18])[CH2:17][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC(=O)O
Reactant: CCCCCCCCOCCCC#N
Agent: Cl
Product: CCCCCCCCOCCCC(=O)O
Yield: 32 %

Procedure:
A solution of 5-oxatridecanonitrile (1.90 g, 9.6 mmol) in a mixture of acetic acid (10 mL) and concentrated HCl (50 mL) was refluxed for 20 h. After evaporation of the solvent in vacuo, water (50 mL) and ethyl acetate (100 mL) were added to the residue. The organic phase was washed with water (2×50 mL), brine (1×50 mL), and then dried over Na2SO4. After distillation (Kugelrohr device, 120°-125° C./0.1 torr) and column chromatography (silica gel) using ethyl acetate:hexane (1:1) as eluent. 5-Oxatridecanoic acid (0.66 g, 32%) was isolated as a colorless oil. IR: 3550-2300, 1700 cm-1, 1H-NMR: 0.78-0.98 (t, 3H), 1.00-1.40 (m, 10H), 1.42-1.62 (p, 2H), 1.82-1.94 (p, 2H), 2.40-2.56 (t, 2H), 3.38-3.52 (m, 4H). Anal. Calcd. for C12H24O3 : C, 66.63, H, 11.18%; Found: C, 66.53, H, 11.14%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][C:14]1[C:19](=[O:20])[N:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]2=[N:16][C:15]=1[CH3:25].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:25][C:15]1[N:16]=[C:17]2[CH2:24][CH2:23][CH2:22][CH2:21][N:18]2[C:19](=[O:20])[C:14]=1[CH2:13][CH:12]=[O:11]
Reactant: Cc1nc2n(c(=O)c1CCO)CCCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc2n(c(=O)c1CC=O)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a stirred mixture of 2.2 mL (25.22 mmoles) of oxalyl chloride in 70 mL of anhydrous methylene chloride at low temperature (−70° C. to −50° C.) and under inert atmosphere, 4.1 mL (57.78 mmoles) of dimethyl sulfoxide were added. Then, a solution of 5 g (24.02 mmoles) of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (X) in 30 mL of methylene chloride was added. After 30 minutes, 14.6 mL (104.75 mmoles) of triethylamine were added and the mixture was warmed for 45 minutes at room temperature. 75 mL of water were poured and the organic phase was decanted. The aqueous phase was removed with methylene chloride. All the organic phases were dried over anhydrous sodium sulphate, filtered and the solvent was evaporated to give 4.90 g (99%) of (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)-acetaldehyde (II) as an oily residue. The compound thus obtained was pure enough as to be used in the subsequent reaction step with no prior purification.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH2:5]([O:7][C:8](=[O:29])[CH:9]=[C:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]=2[NH:11]1)[CH3:6].C(O)(=O)C>O>[CH2:5]([O:7][C:8](=[O:29])[C:9](=[N:1][OH:3])[C:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]=2[N:11]=1)[CH3:6]
Reactant: O=N[O-]
Reactant: CCOC(=O)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium nitrite, 1.5 g. (0.022 mol), was added to a solution of 6.2 g. crude 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid ethyl ester in 75 ml. of glacial acetic acid. After stirring at room temperature for 20 minutes the reaction mixture was diluted with 200 ml. of water. The precipitated product was collected, washed with water and sucked dry to give crude product. The analytical sample was recrystallized from methylene chloride/ethanol to give light yellow crystals with mp 219°-221°.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1Cl.[F:22][C:23]([F:31])([F:30])[CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([C:23]([F:31])([F:30])[F:22])[CH2:25]1
Reactant: FC(F)(F)C1CCCNC1
Reactant: CNc1cc(Cl)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNc1cc(N2CCCC(C(F)(F)F)C2)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(3,3,3-trifluoro-propyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (80 mg, 0.246 mmol), 3-trifluormethyl-piperidine (150 mg, 0.98 mmol), DIPEA (0.34 mL, 2.0 mmol) and dioxane (5 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([C@@H:57]([NH2:66])[CH2:58][CH2:59][C:60]3[CH:65]=[CH:64][N:63]=[CH:62][CH:61]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>CN(C)C=O.ClCCl.C(O)C>[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([C@@H:57]([NH:66][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][CH2:59][C:60]3[CH:65]=[CH:64][N:63]=[CH:62][CH:61]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: N[C@@H](CCc1ccncc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](CCc2ccncc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 34 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(pyridin-4-yl)propylamine in dimethylformamide. Yield: 34%; Rf value: 0.25 (silica gel; dichloromethane/ethanol=9:1); C28H28ClN5O2 (502.02); mass spectrum: (M+H)+=502/504 (chlorine isotope).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>CN(C=O)C.O>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:10][C:8]1[CH:9]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=1[O:11][CH3:12]
Reactant: COc1ccc(F)cc1O
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)cc1Oc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. oil, 0.281 g) was added to a solution of 5-fluoro-2-methoxyphenol (11.0 g) in DMF (20 ml) and stirred at RT for 30 min. 2-Chloro-1-fluoro-4-nitrobenzene (1.23 g) was added and the mixture stirred at RT for 16 h then diluted with water and extracted with diethylether. The organics were dried and evaporated under reduced pressure, yield 1.95 g.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:39])=[C:18]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])=[N:32][CH:33]=2)[C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>ClCCl>[Cl:15][C:16]1[C:17]([CH3:39])=[C:18]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])=[N:32][CH:33]=2)[C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Cyanuric chloride (0.43 g, 2.3 mmol) was added to N,N-dimethylformamide (0.18 mL, 2.3 mmol) at room temperature. After the formation of a white solid (10 minutes), methylene chloride (10 mL) was added, followed by 5-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (0.6 g, 2 mmol). After addition, the mixture was stirred at room temperature overnight, then diluted with dichloromethane and washed with sat. NaHCO3 solution. The organic layers were dried over MgSO4, concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (0.58, 90%). LCMS calculated for C19H23Cl2NO2 (M+H)+: m/z=381.1; Found: 381.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([Si:26]([CH3:29])([CH3:28])[CH3:27])[Si:22]([CH3:25])([CH3:24])[CH3:23])=[C:17]([Cl:30])[CH:16]=1)[OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][C:18]([N:21]([Si:26]([CH3:27])([CH3:29])[CH3:28])[Si:22]([CH3:25])([CH3:24])[CH3:23])=[C:17]([Cl:30])[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC1(C(O)c2ccc(N([Si](C)(C)C)[Si](C)(C)C)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCCC1(C(=O)c2ccc(N([Si](C)(C)C)[Si](C)(C)C)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Yield: 58.6 %

Procedure:
To a stirred solution of 2-butyl-2-{[3-chloro-4-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-phenyl]-hydroxy-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.357 g, 0.678 mmol) in DCM (10 mL) at ambient temperature under nitrogen was added DMP (0.575 g, 1.36 mmol) in a single portion. After one hour the reaction mixture was diluted with DCM, washed with 1 N NaOH and brine, then dried (MgSO4), filtered and concentrated in vacuo to a brown residue (0.290 g). Purification by chromatography (silica, 10% EtOAc in hexanes) gave 2-butyl-2-[3-chloro-4-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-benzoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.208 g, 0.397 mmol, 58%) as a clear colourless residue.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[S:15][C:14]([CH3:16])=[C:13]([C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[O:25][CH2:26][C:27](O)=[O:28])[N:21]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[S:15][C:14]([CH3:16])=[C:13]([C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[O:25][CH2:26][C:27]([N:53]3[CH2:54][CH2:55][N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:49])[CH2:51][CH2:52]3)=[O:28])[N:21]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1sc(C=NNC(=O)OC(C)(C)C)cc1-c1nc(-c2cccc(OCC(=O)O)c2)cs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: Cc1sc(C=NNC(=O)OC(C)(C)C)cc1-c1nc(-c2cccc(OCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2)cs1
Yield: 46.4 %

Procedure:
A stirred solution of 40 mg (0.084 mmol) of 2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid dissolved in dry dimethylformamide (5 mL) was treated with hydroxybenzotriazole (23 mg, 0.17 mmol), 32 mg (0.17 mmol) of N-tert-butoxycarbonyl-piperazine (Lancaster, Windham, N.H., USA), 65 mg (0.17 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) at room temperature for 20 h. The mixture was partitioned between dichloromethane (50 mL) and brine (50 mL). The aqueous layers were extracted twice with dichloromethane (50 mL) and the combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. Purification preparative thin layer chromatography eluting with dichloromethane:methanol 95/5 (v:v) gave tert-butyl 4-(2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperazinecarboxylate (25 mg, 46%) as a white solid. 1H-NMR (DMSO-d6; 300 MHz) δ9.13 (br s, 2H), 8.50 (s, 1H), 8.20 (s, 1H), 7.63 (m, 2H), 7.39 (m, 1H), 6.95 (m, 1H), 4.93 (s, 2H), 3.47-3.34 (m, 8H), 2.82 (s, 3H), 1.45 (s, 9H), 1.42 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C31H39N5O6S2 642.3 (M+H), 542.3 ((M-BOC)+H), 442.3 ((M-2 BOC)+H), found 642.0, 542.2, 442.3.