Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH3:20])(=[O:19])=[O:18].CCOC(C)=O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:9])[C:5]([F:7])([F:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH3:20])(=[O:19])=[O:18])[CH3:2]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CS(=O)(=O)c1ccccc1I
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)c1ccccc1S(C)(=O)=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
To a stirred suspension of Cu(0) (496 mg, 78 mmol) in DMSO (2.5 mL) at room temperature under nitrogen atmosphere was added ethylbromodifluoroacetate (0.5 mL, 39 mmol). The reaction mixture was stirred at 35° C. for 30 min. Then the solution was brought to room temperature and 1-iodo-2-methanesulfonylbenzene (1.0 g, 35 mmol), as prepared in the preceding step, was added. The reaction mixture was stirred at 35° C. for 12 h. The reaction mixture was cooled to room temperature and passed through a bed of Celite using EtOAc to rinse. The filtrate was washed with saturated NH4Cl (50 mL) until the blue color dissipated. The organic phase was then washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to afford 772 mg crude product. The residue was purified by flash column chromatography (20-40% ethyl acetate in hexanes) to yield the desired compound (264 mg, 27%). 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=7.6 Hz, 1H), 7.94 (dd, J=7.7 Hz, 1.7 Hz, 1H), 7.76 (pd, J=7.6 Hz, 1.5 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.15 (s, 3H), 1.29 (t, J=7.1 Hz, 3H). LC/MS (m/z) [M+1]+ 279.3 (calculated for C11H13F2O4S, 279.3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=O)=[N:4][CH:5]=[C:6]([N:8]([CH:10]2[CH2:13][CH2:12][CH2:11]2)[CH3:9])[N:7]=1.[CH2:16]([NH:23][CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:16]([N:23]([CH2:14][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH:10]2[CH2:11][CH2:12][CH2:13]2)[CH3:9])=[CH:5][N:4]=1)[CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(c1cnc(C=O)c(Cl)n1)C1CCC1
Reactant: COC[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC[C@H](O)CN(Cc1ccccc1)Cc1ncc(N(C)C2CCC2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 3-chloro-5-[cyclobutyl(methyl)amino]pyrazine-2-carbaldehyde (451 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (469 mg) and acetic acid (343 μL) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (636 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise a saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (674 mg, 83%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[C:28]([OH:32])(=[O:31])[CH:29]=[CH2:30]>[Cl-].C[N+](C)(C)C>[C:28]([O:32][CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)O
Reactant: c1ccc(OCC2CO2)cc1
Agent: C[N+](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Product: C=CC(=O)OCC(O)COc1ccccc1

Procedure:
To 3000 g of phenyl glycidyl ether (epoxide content 6.16 equiv./kg) containing 9 g of tetramethylammonium chloride and 6 g of 2,6-di-t-butyl-p-cresol, stirred at 100°, was added 1332 g of acrylic acid over one hour. The mixture was stirred at 100° for a further 4 hours, by which time the epoxide content was 0.91 equiv./kg and the viscosity was 60 cP at 25°, to yield 3-phenoxy-2-hydroxypropyl acrylate.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[O-]CCCC.[K+]>C(O)(C)C>[C:30]1([CH:29]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: CCCC[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(O)CCCCC=Cc1ccccc1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
5-Carboxypentyl-triphenylphosphonium bromide (20 g) and benzaldehyde (5.6 g) were suspended in isopropanol (100 ml). To the suspension was added potassium butoxide (10.8 g) in limited amounts at 25° C., then the reaction was allowed to proceed for 2 hours at 70° C. Isopropanol was distilled off under reduced pressure. To the residue was added water (100 ml) to make a solution, which was acidified with hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography to afford 7-phenyl-6-heptenoic acid (7.6 g) as a colorless oily product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([N:11]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:12](=O)[CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B#B.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([N:11]([NH:18][C@@H:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:12][CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](NN1C(=O)CO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21)c1ccccc1
Agent: B#B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NN1CCO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.32 g of cis-8-tert-butoxycarbonyl -5-[(1R)-1-phenylethylamino]-4-oxo-2-oxa-5,8-diazabicyclo[4.3.0]nonane 13b in 6 ml of tetrahydrofuran was added 19.2 ml of 1M diborane tetrahydrofuran complex dropwise under ice-cooling. The mixture was stirred at room temperature overnight. To the mixture was added 5 ml of the diborane solution mentioned above and the mixture was stirred at room temperature for 2 hours. To an ice-cooled reaction mixture was added water and saturated potassium carbonate aqueous solution. The mixture was extracted by ethyl acetate. The organic layer was washed by saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. A residue was subjected to silica gel column chromatography. From an eluant of a mixture of hexane and ethyl acetate (3:1 by volume), the titled compound 14b weighing 2.17 g was obtained.
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:10])[O:7][CH2:8]Cl)[CH:2]([CH3:4])[CH3:3].[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O-:37])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17].[Na+]>>[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O:37][CH2:8][O:7][C:6]([N:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:10])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)CN(CC(C)C)C(=O)OCCl
Agent: [Na+]
Product: CC(C)CN(CC(C)C)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 71.5 %

Procedure:
In the same manner as in step b) in Example 125, 242 mg of the title compound was prepared from 159 mg of chloromethyl N,N-diisobutylcarbamate and 241 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]#[N:29])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].[N:30]([O-])=O.[Na+]>O.O1CCOCC1.Cl>[CH3:9][N:8]1[C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=3)[N:4]=[C:3]([C:28]#[N:29])[C:2]=2[N:1]=[N:30]1
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCc3ccncc3)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCc4ccncc4)c(C(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To a suspension of 3-amino-4-(methylamino)-6-(4-(pyridin-4-ylmethoxy)-3-(trifluoromethyl)phenyl)picolinonitrile (580 mg) in water (5 ml) and 1,4-dioxane (5 ml), 2N hydrochloric acid (1.089 ml) was added at 0° C. and sodium nitrite (145 mg) in water (1 ml) was added then stirred at 0° C. for 10 min then at 20° C. for 70 h. The reaction mixture was filtered, washed with water, dried in vacuum oven to give 410 mg brown solid. Purified by Biotage SNAP cartridge KP-Sil column (25 g, dichloromethane:methanol=1:0, 20:1 to 10:1) then passed through Strata SCX column (20 g) to give 495 mg brown solid as 1-methyl-6-(4-(pyridin-4-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (83%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(CBr)c1
Temperature: 90 °C
Reaction time: 96 h
Yield: 104.9 %

Procedure:
To a solution of 2-methyl-4-nitrobenzotrifluoride (5.05 g, 24.6 mmol, synthesised according to Journal of medicinal chemistry (1996), 39(23), 4608-4621) in carbon tetrachloride (50 ml) was added NBS (4.77 g, 26.8 mmol, Aldrich) and then benzoyl peroxide (0.110 g, 0.454 mmol, Acros). The mixture was heated to 90° C. overnight, cooled to ambient temperature and the allowed to stand for 4 days. The suspension was filtered and the residue washed with carbon tetrachloride (10 ml). The solvent was removed in vacuo to give 2-(bromomethyl)-4-nitro-1-(trifluoromethyl)benzene as a mobile orange oil (7.33 g).
Reaction SMILES: C(O)(C)(C)C.CC(C)([O-])C.[Na+].[C:12]1([C@@H:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:12]1([C@@H:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N[C@@H](C)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@H]1CCCC[C@@H]1N[C@@H](C)c1ccccc1
Temperature: 9 °C
Yield: 97.5 %

Procedure:
Tetrahydrofuran (1.25 L) was charged to a reactor followed by t-butanol (150 mL), and sodium t-butoxide (313 g) under nitrogen at ambient temperature. Additional tetrahydrofuran (1.0 L) was added and then the contents were cooled to <10° C. A solution of (1R,2S)-ethyl 2-((S)-1-phenylethylamino)cyclohexane carboxylate (9, 243.9 g) in tetrahydrofuran (300 mL) was added in NLT 30 minutes, while maintaining the temperature between 6-12° C. After the addition was complete, the mixture was warmed to 22° C. in NLT 30 minutes and further mixed for NLT 4 hours under nitrogen. The contents were cooled to <10° C. and the reaction was quenched with a solution of ammonium chloride (269.3 g) and water in NLT 30 minutes, while maintaining the temperature between 6-12° C. The lower aqueous layer was separated and extracted with 750 mL of heptanes. The upper organic layer was concentrated to about 0.8 L volume and extracted with the heptanes solution. The aqueous layer was separated and extracted with fresh heptanes (2×0.75 L) and the combined organic layers were washed with water (2×0.75 L) and 3.5 M aqueous sodium chloride solution (0.75 L), and dried with anhydrous magnesium sulfate. Concentration of the organic layer under vacuum gave 237.9 g of (1S,2S)-ethyl 2-((S)-1-phenylethyl amino)cyclohexane carboxylate (10) as a major isomer.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5].[Li][CH3:17].[NH4+].[Cl-].O>C1COCC1>[NH:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4](=[O:5])[CH3:17])[C:14]=2[N:13]=[CH:12]1
Reactant: CON(C)C(=O)c1cccc2[nH]cnc12
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc2[nH]cnc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred solution of 1H-benzoimidazole-4-carboxylic acid methoxy-methyl-amide (742 mg, 3.62 mmol) in THF (36 mL) at −78° C. was added MeLi (1.6M; 2.49 mL, 3.98 mmol) dropwise. The mixture was stirred at −78° C. for 2 hours before an additional 1.0 mol. eq. MeLi (2.3 mL) was added dropwise. The mixture was stirred at −78° C. for a further 2 hours before saturated aqueous NH4Cl solution was added and the mixture warmed to room temperature. Enough water was added to dissolve all solids and the phases were separated. The aqueous phase was extracted into CHCl3 (×3), dried and concentrated in vacuo to give a white solid. Trituration with EtOAc (5 mL) followed by collection by filtration and washing with 4:1 Et2O/EtOAc (5 mL) provided 1-(1H-benzoimidazol-4-yl)-ethanone (487 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[NH4+].[Cl-].O>[Fe].CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc(Cl)cc2cccnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)cc2cccnc12
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 6.30 g (30.3 mmol) 6-chloro-8-nitroquinoline, 14.7 g (272 mmol) NH4Cl, 120 mL H2O and 250 mL EtOH is added 5.0 g (90.6 mmol) Fe powder, and the resulting mixture is refluxed for 2.5 h. The volatiles are evaporated, and the residue is stirred in mixture of 200 mL CH2Cl2 and 300 mL water for 30 min. The resulting bi-phasic solution is filtered through celite, the layers are separated, and the aqueous layer is extracted 2×100 mL CH2Cl2. The combined organics are washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. Flash chromatography on SiO2, eluting with hexanes/EtOAC (10/1 to 4/1), gives 2.80 g (15.7 mmol, a 52% yield) of the title compound as a tan solid. mp: 70-73° C.; MS (ES) m/z 179 (MH)+.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>C1COCC1>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12]=1[C:13]#[N:14]
Reactant: OC1CCCCC1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N)cccc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a solution of cyclohexanol (19.1 g, 0.191 mol) in anhydrous THF (500 mL) was added NaH (7.6 g, 40% in mineral oil, 0.191 mol) in small portions at 0° C. under nitrogen. The mixture was stirred at room temperature for 1 h and a solution of 2-amino-6-fluorobenzonitrile (20.0 g, 0.15 mol) in anhydrous THF (150 mL) was added drop-wise at room temperature. The reaction mixture was heated to reflux overnight then cooled to room temperature and most of the THF removed under reduced pressure. Ice water (100 mL) was added to the concentrated reaction mixture followed by EtOAc (500 mL). The organic layer was separated and successively washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 25-30% EtOAc in hexanes to give 2-amino-6-(cyclohexyloxy)benzonitrile as a light yellow oil (17.9 g, 56%). 1H NR (400 MHz, CDCl3) δ 1.32-1.43 (m, 3H), 1.51-1.55 (m, 1H), 1.62-1.69 (m, 2H), 1.79-1.95 (m, 4H), 4.31-4.36 (m, 3H), 6.23-6.27 (m, 2H), 7.18 (d, J=8.0 Hz, 1H). MS 329 (WO.
Reaction SMILES: [Br-:1].[NH4+].CC1C=CC(S(O[C:14]2[CH2:18][CH:17]([C:19](=[O:36])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[C:28](=[O:35])[NH:29][CH:30]([CH:32]3[CH2:34][CH2:33]3)[CH3:31])[N:16]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=3)[N:15]=2)(=O)=O)=CC=1.CN(C)C=O>O>[Br:1][C:14]1[CH2:18][CH:17]([C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28](=[O:35])[NH:29][CH:30]([CH:32]2[CH2:34][CH2:33]2)[CH3:31])=[O:36])[N:16]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[N:15]=1
Reactant: Cc1ccc(S(=O)(=O)OC2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)cc1
Reactant: [Br-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Temperature: 93 °C
Yield: 12.9 %

Procedure:
0.54 g of ammonium bromide was added to a mixed liquid comprising 1.0 g of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl 4-methylbenzenesulfonate and 25 ml of N,N-dimethylformamide, followed by heating to 93° C. One hour later, the reaction liquid was poured to 50 ml of water, followed by extraction with diethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 0.11 g of the desired product in the form of a paste.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:12]1([CH2:18][CH2:19][NH:20][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NCCN1CCOCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(NCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 48 h
Yield: 20.9 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 2-(4-morpholinyl)-ethylamine (2.8 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 48 h. The reaction mixture was cooled to room temperature, poured into water (200 mL) and extracted with dichloromethane (CH2Cl2) (250 mL). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 4×15 cm, eluted with 90:10 EtOAc/MeOH) to yield the product as an orange solid (0.39 g, 20%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NC([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([O:42][CH2:43][CH3:44])[CH:34]=3)[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24]2=[O:45])[CH2:19][CH2:18]1)=O)(C)(C)C>>[C:1]1([NH:7][C:8]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[N:32]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([O:42][CH2:43][CH3:44])[CH:34]=4)[C@@H:30]4[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]4)[C:24]3=[O:45])[CH2:19][CH2:18]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOc1ccc(C2=NN(C3CCN(C(=O)NC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)Nc4ccccc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from starting compound A2 and phenylisocyanate as described for compound 6. Crystallisation from ether. M.p. 109-112° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[O-]S([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH:28]=O>C(Cl)Cl>[C:2]([O:6][C:7](=[O:11])[C@@H:8](/[N:9]=[CH:28]/[CH2:27][C:26]([CH3:31])([CH3:30])[CH3:25])[CH3:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)CC=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](/N=C/CC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A mixture of L-alanine tert-butyl ester hydrochloride (Bachem) (1.8 g, 10 mmol) and MgSO4 in CH2Cl2 (100 mL) was added triethylamine (1.5 g, 15 mmol). The mixture was stirred at room temperature for 1 h, and 3,3-dimethyl-butyraldehyde (1 g, 10 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered, and the filtrate was washed with water, brine, and concentrated. The residue was dried under reduced pressure to give (S)-2-[3,3-dimethyl-but-(E)-ylideneamino]-propionic acid tert-butyl ester as colorless oil (2.3 g, 100%) which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[C:15]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (0.10 g, 0.50 mmol) was combined with acetic anhydride (0.052 mL, 0.55 mmol) and triethylamine (0.21 mL, 1.5 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The resulted residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give tert-butyl 4-(acetylamino)piperidine-1-carboxylate, LCMS [M+Na]+: m/z=265.1. The later was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give crude HCl salt product (0.057 g), which was used directly in the next step. LCMS calculated for C7H15N2O (M+H)+: m/z=143.1; Found: 143.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[C@@H:17]([CH:19]([CH3:21])[CH3:20])[NH2:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:23][CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:20][CH:19]([C@H:17]1[NH:18][C:26](=[O:28])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:10][CH:11]=2)[C:16]1=[O:22])[CH3:21]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)C)cc2)ccc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)N[C@H](C(C)C)C3=O)cc2)ccc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 174.4 %

Procedure:
To a solution of N1-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-D-valinamide (Intermediate 83, 65 mg) in dry dichloromethane (10 mL), TEA (0.138 mL, 0.990 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (26.4 mg, 0.089 mmol) in dry dichloromethane (3 mL) was slowly added and the reaction mixture was stirred for 1 hour at 0° C. The reaction was quenched with water (2 mL) and a saturated aqueous solution of ammonium chloride (5 mL) and was extracted with dichloromethane (2 times 10 mL). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by silica gel flash chromatography (Biotage system, 10 g SNAP column) using as eluent a gradient cyclohexane/ethyl from 100/0 to 60/40 to afford the title compound as a white solid (55 mg).