Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][C:10]=2[CH3:14])O1.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]2)[CH:20]=[N:19][CH:18]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:30][C@H:25]1[O:26][C@@H:27]([CH3:29])[CH2:28][N:23]([C:21]2[CH:20]=[N:19][CH:18]=[C:17]([C:9]3[CH:13]=[CH:12][O:11][C:10]=3[CH3:14])[N:22]=2)[CH2:24]1
Reactant: C[C@@H]1CN(c2cncc(Cl)n2)C[C@H](C)O1
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
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: O
Solvent: C1COCCO1
Product: Cc1occc1-c1cncc(N2C[C@@H](C)O[C@@H](C)C2)n1
Temperature: 100 °C

Procedure:
4,4,5,5-Tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane (567 mg, 2.72 mmol) was added to a solution of cis-4-(6-chloro-2-pyrazinyl)-2,6-dimethylmorpholine (620 mg, 2.72 mmol) in a mixture of 1,4-dioxane (17 mL), water (2.83 mL) and sodium carbonate (577 mg, 5.45 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (315 mg, 0.272 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. for 1 hour. Crude LCMS shows desired product and starting material so the reaction mixture was stirred and heated for a further 1 hour at 100° C. in the microwave. Crude LCMS shows desired product and no starting material can be seen. The reaction mixture washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜5 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound (441 mg, 1.533 mmol, 56.3% yield). LC/MS [M+H]+=274.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10]=1[C:20]([OH:22])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN>C1COCC1>[CH3:23][NH:24][C:20]([C:10]1[N:11]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:22]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2)nc1C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CNC(=O)c1nc(-c2ccccc2)sc1NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 6 h

Procedure:
A solution of 5-tert-butoxycarbonylamino-2-phenyl-thiazole-4-carboxylic acid (138 mg, 0.43 mmol) in THF (2.5 ml) was treated with HATU (187 mg, 0.49 mmol), N-methylmorpholin (0.25 ml, 2.24 mmol) and methylamine (0.29 ml, 2M THF solution) and stirred at 75° C. for 6 h. The reaction mixture was partitioned between potassium hydrogen sulfate (10% aqueous solution) and ethyl acetate and extracted. The organic layer was washed with water, sodium bicarbonate and brine. The combined organic phases were dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (98 mg, 65%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)[C@H:3]([OH:6])[CH2:4]Cl.[OH-].[K+].O>C(O)C>[F:15][C:10]1[CH:9]=[C:8]([CH2:7][C@H:2]([NH2:1])[C@H:3]2[CH2:4][O:6]2)[CH:13]=[C:12]([F:14])[CH:11]=1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reaction time: 0.5 h

Procedure:
(1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylamine (EXAMPLE 17, 33 mg, 0.14 mmol) and absolute ethanol (1.5 mL) are mixed. Potassium hydroxide (9.8 mg, 0.175 mmol) in absolute ethanol (0.5 mL) is added to this mixture and the resulting mixture is stirred at 20-25 deg for 30 min. At this time ESMS indicates formation of the product (MH+=200.1). Water (2 mL) is added and mixture is concentrated under reduced pressure to half the volume and then diluted with ethyl acetate (15 mL). The organic phase is separated and the aqueous phase is extracted with ethyl acetate (2×10 mL). The organic phases are combined, washed with saline and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to give the title compound, MH+=200.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:30])([F:29])[CH2:27]I>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:27][C:26]([F:30])([F:29])[F:25])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CC(F)(F)F
Temperature: 70 °C
Reaction time: 18 h
Yield: 33.5 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.4 g, 1.311 mmol), potassium carbonate (0.544 g, 3.93 mmol) and 1,1,1-trifluoro-2-iodoethane (0.826 g, 3.93 mmol) in DMF (2 ml) was heated at 70° C. under stirring for 18 h The reaction mixture was cooled down and diluted with water (15 ml) and extracted with DCM (15 mlX3). The combined organic phase was washed with water (25 ml) and dried with Na2SO4 and concentrated. The residue was purified by column chromatography (biotage 25 g) eluted with ethyl acetate/cyclohexane 0-60% to afford product 6-bromo-7-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.17 g) 1H NMR (500 MHz, CDCl3) 7.45-7.50 (m, 3H), 7.38-7.40 (m, 2H), 7.28 (s, 1H), 4.94 (s, 2H), 4.55 (q, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]3[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]3[CH3:14])[CH:7]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(C)n1-c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 30 %

Procedure:
To a stirred solution of 1-(5-chloro-2-nitro-phenyl)-2,5-dimethyl-1H-pyrrole (73 mg, 0.29 mmol, as prepared in the previous step) in DMF (2 mL) was added piperazine-1-carboxylic acid tert-butyl ester (542 mg, 2.9 mmol) and the result was heated to 90° C. for 18 h. The reaction a diluted with EtOAc (50 mL), washed with H2O (2×25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was chromtographed on a SPE column (5 g, SiO2) to afford 35 mg (30%) of the title compound as a brown solid. 1H-NMR (CDCl3; 400 MHz): δ 8.13 (d, 1H, J=9.3 Hz), 6.91-6.88 (m, 1H), 6.66 (s, 1H), 5.93 (s, 2H), 3.63-3.60 (m, 4H), 3.42-3.40 (m, 4H), 1.97 (s, 6H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 77 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (1.202 g) and 2-bromo-4'-chloroacetophenone (2.114 g) in triethylamine (2 ml) and ethanol (20 ml) was stirred at ambient temperature for 75 mins. The resulting suspension was filtered, the solid was washed with water then crystallised from acetone to give the title pyrimidinone (1.973 g,); m.p. 216°-218°; λmaxEtOH 252 nm (ε 22360), 233 nm (ε 2080), λinf 288 nm (ε 1530).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(F)c(F)c3)cccc2c1N
Yield: 95.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3,4-difluorophenyl boronic acid (202 mg, 1.28 mmol) were reacted to afford the title compound (108 mg, 98.7% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.89 (dd, J=7.9 Hz, J′=1.9 Hz, 1H), 7.68-7.80 (m, 2H), 7.48-7.59 (m, 1H), 7.37-7.45 (m, 1H), 7.23-7.33 (m, overlapped with CHCl3), 3.47 (q, J=6.7 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=343 (M+H) HPLC 2.01 min.
Reaction SMILES: C1(=O)[N:5]([C@@H:6]([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8])C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][C@@H:6]([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@H](CCC(OC)OC)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](N)CCC(OC)OC
Temperature: 25 °C
Reaction time: 144 h

Procedure:
(S)-2-Phthalimido-5,5-dimethoxypentanoic acid, methyl ester [prepared as described in Example 4(f), 3.35 g., 10.43 mmol.) in methanol (70 ml.) was treated with hydrazine monohydrate (531 μl., 10.95 mmol., 1.05 eq.) and the solution was stirred at room temperature for 6 days. The mixture was filtered and the solid was washed with methanol. The filtrate was concentrated, triturated with methylene chloride, filtered again, concentrated, and dried in vacuo to yield 1.89 g. of title product as a cloudy oil. TLC (10% methanol in methylene chloride) Rf =0.39.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])=[CH:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
151 mg of 4-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 105 μL of propane-2-sulfonyl chloride and 205 μL DIPEA in 500 μL DCM. The reaction mixture was evaporated, subjected to basic workup conditions and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1-methylethylsulfonamido)benzamide. MS (Q1) 430 (M)+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][NH:13][CH2:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:3]1=[O:28].CCN(C(C)C)C(C)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][N:13]([CH2:14][CH:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:44]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:45])[C:3]1=[O:28]
Reactant: Cn1c(=O)c(CNCC(c2ccccc2)C2CCOCC2)cc2ccccc21
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)c(CN(CC(c2ccccc2)C2CCOCC2)C(=O)C2CCCCC2)cc2ccccc21
Reaction time: 1 h

Procedure:
To 1-methyl-3-({[2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl]amino}methyl)quinolin-2(1H)-one (46.5 mg, 0.124 mmol) in CH2Cl2 (3 ml) and added DIEA (0.043 ml, 0.247 mmol) then cyclohexanecarbonyl chloride (0.018 ml, 0.136 mmol). The reaction was stirred for 1 hour and then concentrated in vacuo. Purified by reversed-phase chromatography (15-75% ACN in water (with 0.5 ml/l NH4OH), 20×100 mm Phenomenex Gemini C18 column). Desired fractions were concentrated in vacuo. HRMS [M+H]1+ 487.2962. 400 MHz 1H NMR (CDCl3) δ 7.59-7.47 (m, 2 H), 7.37 (d, J=8.52 Hz, 1 H), 7.33-7.13 (m, 7 H), 4.26 (d, J=18.4, 1 H), 4.17-3.95 (m, 2 H), 3.88-3.76 (m, 2 H), 3.74 (s, 3 H), 3.44-3.23 (m, 3 H), 2.97-2.91 (m, 0.8 H, rotational isomer A), 2.67-2.62 (m, 0.2 H, rotational isomer B), 2.42-2.19 (m, 0.2 H, rotational isomer B), 2.15-2.08 (m, 0.8 H, rotational isomer A), 1.95-0.95 (m, 15 H). 29.4 mg, 49%.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH2:11][C@H:10]2[N:7]([C:8](=[O:15])[C@@H:9]2[C@H:12]([OH:14])[CH3:13])[C:6]=1[C:16]([OH:18])=[O:17])[CH2:3][NH2:4].Cl.[C:20](=N)(OCC)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[OH:14][C@@H:12]([C@H:9]1[C:8](=[O:15])[N:7]2[C@@H:10]1[CH2:11][C:5]([C@H:2]1[CH2:3][NH:4][C:20]([CH3:21])=[N:1]1)=[C:6]2[C:16]([OH:18])=[O:17])[CH3:13]
Reactant: CCOC(C)=N
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C([C@H](N)CN)C[C@H]12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1=N[C@@H](C2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)CN1
Yield: 7.3 %

Procedure:
To a solution of (5R,6S)-3-[(1S)-1,2-diaminoethyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.00 g) in a mixture of water (100 ml) and tetrahydrofuran (100 ml) was added portionwise ethyl acetimidate hydrochloride (1.00 g) under ice-cooling with stirring, keeping the pH between 8.0 and 8.5 with saturated aqueous potassium carbonate. After stirring for 2 hours, the mixture was concentrated under reduced pressure to be about 10 ml-volume. The aqueous solution was subjected to a column chromatography on silica gel (100 g) and eluted with a mixture of water and acetonitrile (6:4, V/V). The fractions containing the object compound were collected, concentrated under reduced pressure, and lyophilized to give a solid. A solution of the solid in water (10 ml) was subjected to a column chromatography on "Diaion HP-20" and eluted with water. The fractions containing the objected compound were collected, concentrated under reduced pressure, and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(4S)-2-methyl-2-imidazolin-4-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.08 g) as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[O:14]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Sc1ccccc1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCC(=O)c1ccc(Sc2ccccc2)cc1
Temperature: 110 °C
Yield: 75.5 %

Procedure:
4-(4-Fluoro-phenyl)-4-oxo-butyric acid (10.0 g, 51 mmol), thiophenol (5.2 g, 51 mmol) and powdered potassium carbonate (13.8 g, 100 mmol) were added to 25 mL of dimethyl sulfoxide (DMSO). The reaction mixture was heated to 110° C. for 2 hours, then cooled and diluted by addition of 250 mL water. The aqueous mixture was extracted three times with 100 mL of EtOAc, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to yield 11 g (38.5 mmol, 75.5%) of 4-oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid as a crude solid. MS: 287 (M+H)+.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]=[CH2:23])=[O:20]>C(Cl)(Cl)Cl>[C:19](=[O:20])([O:21][CH:22]=[CH2:23])[O:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]1
Reactant: CC(C)(C)C1CCC(O)CC1
Reactant: C=COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=COC(=O)OC1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.4 %

Procedure:
To a 250 mL 3-neck round bottom flask fitted with a magnetic stirrer, condenser, thermometer, ice water bath, dropping funnel, was added 10.0 g (64.0 mmol) of 4-t-butylcyclohexanol, 5.6 g (70.3 mmol) of pyridine and 100 mL of chloroform. The reaction mixture was cooled to less than 10° C. and 6.8 g (64.0 mmol) of vinyl chloroformate was added so that the temperature remained below 15° C. The reaction mixture was stirred at room temperature for 20 hours, then washed with 100 mL 2N HCl, 100 mL distilled water and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting oil chromatographed (silica gel, methylene chloride) to afford 7.3 g (32.28 mmol, 50.4%) of an oil. FTIR (neat, capillary) 2949.85, 2867.24, 1753.81, 1650.71, 1478.96, 1468.77, 1452.57, 1393.73, 1385.90, 1361.15, 1325.03, 1296.75, 1246.94, 1193.82, 1178.29, 1155.10, 1118.52, 1106.53, 1083.32, 1041.01, 1016.58, 1005.94, 946.14, 923.71, 902.63, 867.23, 843.74, 804.43, 783.98, 758.83, 696.74, 668.14. NMR (CDCl3) δ 6.86-7.22 (1H,m), 4.37-4.97 (2H,m), 1.00-2.30 (10H,m), 0.85 (9H,S). ##STR42##
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:21]2[CH:26]=[C:25]([CH2:27][OH:28])[CH:24]=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)#[N:7].C(N(C(C)C)C(C)C)C>C1COCC1>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:21]2[CH:26]=[C:25]([CH2:27][O:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:24]=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)#[N:7]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CO)cc(OCC)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(COS(C)(=O)=O)cc(OCC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulphonyl chloride was added slowly at 0° C. to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxymethyl-phenyl)-acetate (200 mg, 0.564 mmol) obtained in Example 234.2 and N-ethyldiisopropylamine (88 mg, 0.68 mmol) in THF (3 ml). The mixture was stirred for 1.5 h. at 0° C. and for 1.5 h. at room temperature. The mixture was poured into ice-water/1M HCl and extracted with EtOAc. The organic phase was washed with H2O, dried and filtered, and the filtrate was concentrated. There were obtained 232 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-methanesulphonyloxymethyl-phenyl)-acetate as a yellow oil, which was used for the next reaction without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[NH:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[H-].[Na+].Cl[C:26]([O:28][CH3:29])=[O:27].O>CN(C)C=O>[CH3:29][O:28][C:26](=[O:27])[NH:22][C:14](=[N:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][C:4]=1[Cl:12])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19]
Reactant: N=C(Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)C(F)(F)F
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)NC(=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)C(F)(F)F
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
First, 0.18 g (0.50 mmol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,3,3,3-pentafluoropropionamidine as present compound 4 was dissolved in 10 ml of N,N-dimethylformamide, to which 0.04 g (1.0 mmol) of sodium hydride (about 60% in oil) was added under ice cooling, and the mixture was stirred for 10 minutes. Then, 0.05 g (0.50 mmol) of methyl chloroformate was added to the reaction mixture, which was stirred at room temperature for 6 hours. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.08 g of [1-(2,6-dichloro-4-trifluoromethylphenylimino)-2,2,3,3,3-pentafluoropropyl]carbamic acid methyl ester (hereinafter referred to as present compound 60).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C.O>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)O)c(F)c1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)O)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-amino-2-fluoro-benzoic acid (5.61 g, 36.2 mmol) and acetic anhydride (5.13 mL, 54.3 mmol) in 60 mL acetic acid was stirred at 60° C. overnight. The mixture was taken up in 250 mL water and stirred for 30 min. The precipitate was filtered and washed with water. The filtrate was washed with ethyl acetate. The organic phase was neutralized with sat. K2CO3 (aq) and concentrated i.vac. A small volume was left, the precipitate was filtered and combined with the first isolated precipitate.
Reaction SMILES: [OH:1][B:2]([OH:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH2:13](O)[CH2:14]CO>C1(C)C=CC=CC=1>[O:1]1[CH2:14][CH2:13][O:12][B:2]1[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: OCCCO
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(B2OCCO2)cc1
Reaction time: 6 h

Procedure:
A mixture of 4-(dihydroxyboryl)benzoic acid (30.00 g, 181 mmol) and 1,3-propanediol (15.20 g, 200 mmol) in toluene (750 mL) at 140° C. was stirred for 6 hours while collecting the water removed by azeotrope formation. The mixture was concentrated to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[S:31]1[C:35]([C:36]([NH:38][NH2:39])=O)=[N:34][CH:33]=[N:32]1.ClCCl.CO>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:36]([C:35]3[S:31][N:32]=[CH:33][N:34]=3)=[N:38][N:39]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Reactant: NNC(=O)c1ncns1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Cl)c1Cl)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 120 °C

Procedure:
4-[(2,3-Dichloro-4-fluorophenyl)carbonyl]-2-piperazinone (I34) (0.25 g, 0.859 mmol) was dissolved in dichloromethane (DCM) (2.147 ml) and stirred under an argon atmosphere. Triethyloxonium tetrafluoroborate (0.196 g, 1.031 mmol) was added and the solution was left to stir for 40 minutes. A clear solution formed. 1,2,4-Thiadiazole-5-carbohydrazide (I80) (0.149 g, 1.031 mmol) was added and the solution was left to stir under argon for 60 minutes and then the solvent was removed under reduced pressure. 1-Butanol (2.147 ml) was added and the solution was left to reflux at 120° C. under an argon atmosphere for 5 hours. The solvent was removed under reduced pressure to afford a crude light orange solid of 0.56 g. TLC (DCM/MeOH 90:10): showed amide remained but some product had been formed. The crude material was purified by flash chromatography (Biotage SP4, 50 g cartridge) with a gradient of MeOH 0-10% in DCM. The solvent was removed under reduced pressure to afford desired product but still containing some impurities. The isolated material was then purified by MDAP and the solvent was removed under reduced pressure and transferred to a vial. The material was triturated with ether to afford desired product in 5.7 mg.