Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([NH:7][CH2:8][C:9]1[C:17]2[NH:16][C:15]3[CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:6].O>CN(C=O)C>[CH2:4]1[N:16]2[C:17]3[C:13]([C:14]4[CH2:20][CH2:19][CH2:18][C:15]=42)=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:8][NH:7][C:5]1=[O:6]
Reactant: O=C(CCl)NCc1cccc2c3c([nH]c12)CCC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cn2c3c(c4cccc(c42)CN1)CCC3
Reaction time: 16 h
Yield: 57.5 %

Procedure:
To a suspension of NaH (124 mg, 3.10 mmol) in DMF (3 mL), 2-chloro-N-(1,2,3,4-tetrahydrocyclopenta[b]indol-5-ylmethyl)acetamide (135 mg, 0.515 mmol) in DMF (3 mL) was added at rt under Ar. After 16 h, H2O (2 mL) was added to quench the excess reagent, H2 evolved upon addition. After an additional 30 min, CHCl3 (20 mL) and H2O (10 mL) were added. The two layers were separated. The aqueous layer was extracted with CHCl3 (10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification on SiO2, eluted with (30:1) CHCl3:CH3OH gave 67 mg (58%) of the title compound as a brown solid.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:38]=[CH:37][CH:36]=[CH:35][C:8]=1[C:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30]C(=O)C)=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:10])(=O)C.CO.C(O)(=O)C>O>[C:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:34])[C:24]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[OH:30])=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:8]1[C:7](=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:6]
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2OC(C)=O)ccc1NC(=O)c1ccccc1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(NC(=O)c2ccccc2O)c(C(=O)O)c1)c1ccccc1O
Temperature: 25 °C
Yield: 82.5 %

Procedure:
An aqueous solution of 4 g of sodium hydroxide in 10 ml of water was added to a mixture of 5.3 g of methyl 2,5-bis(2'-acetoxybenzamido)-benzoate obtained in Example 3 and 100 ml of methanol. The resulting mixture was stirred at room temperature for 20 - 30 hours and then poured into 500 ml of water containing 10 ml of acetic acid to precipitate crystals. The crystals were recovered by filtration, washed with water and recrystallized from a mixture of dioxane and water to yield 3.5 g of 2,5-bis(salicylamido)-benzoic acid having a melting point between 280° - 283°C (decomposition).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N+:9]([O-])[CH:10]=1.C(Cl)(=O)C1C=CC=CC=1.C[Si]([C:30]#[N:31])(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([C:30]#[N:31])=[N:9][C:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)C#N
Reactant: COCOc1ccc(CC(C)(C)C)[n+]([O-])c1
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Product: COCOc1ccc(CC(C)(C)C)nc1C#N
Reaction time: 4 h
Yield: 73.6 %

Procedure:
5-(Methoxymethoxy)-2-neopentylpyridine-N-oxide (11.5 g, 51 mmol) was dissolved in CH2Cl2 (50 mL) to which benzoyl chloride-(12 ml, 102 mmol) and (trimethylsilyl)formonitrile (14 ml, 102 mmol) were added. The mixture was stirred under N2 4 h, quenched with saturated NaHCO3 (150 mL), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with saturated NaHCO3 (2×50 mL), dried (MgSO4), and evaporated to give the crude product as a brown oil, which was purified by ISCO (330 g SiO2, 0-40% EtOAc/Hexane) to give 3-(methoxymethoxy)-6-neopentylpicolinonitrile (8.8 g, 74% yield) as a clear oil.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH4+].[Cl-].Cl>[Zn].C1COCC1>[F:13][C:7]([F:14])([CH:1]([OH:5])[CH2:2][CH2:3][CH3:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CCCC=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)C(F)(F)C(=O)OCC
Temperature: 25 °C

Procedure:
To a mechanically stirred mixture of zinc (108 g, 1.66 mol), n-butanal (100 g, 1.39 mol), CeCl3.7H2O (10.14 g, 0.027 mol) and anhydrous THF (1.3 L) at about 25° C. was added ethyl 2-bromo-2,2-difluoroacetate (SM1, 33.8 g, 0.167 mol) under N2. The mixture was stirred at about 25° C. until the reaction had initiated, then SM1 (304 g, 1.50 mol) was added dropwise at 35° C. without external heating. After the addition completed, the mixture was stirred at 20˜35° C. until n-butanal was less than 2.0%. The reaction mixture was then cooled to about 5° C. and sat. aq. NH4Cl (800 mL) was added slowly at about 5° C., and then adjust pH 3.0 with 6 N HCl. The mixture was stirred for 15 min. and then filtered through a plug of celite; the filter cake was washed once with MTBE (1 L). The combined filtrate was then separated and the aqueous layer was extracted once with MTBE (1 L). The combined organic layers were washed once with sat. aq. NaHCO3 (1 L), once with sat. aq. NH4Cl (1 L) and then concentrated at <50° C. under reduced pressure to give 281 g of crude IM1 with 80% GC purity. The crude IM1 was purified by vacuum distillation to provide 160 g IM1 with 98% GC purity in 58% GC total yield.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)=[O:4].N12CCCN=C1CCCCC2.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>CN(C)C=O.C(#N)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[O:4])=[CH:7][C:8]=1[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C(Cl)(Cl)Cl
Reactant: Nc1ccc(O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 115 °C
Yield: 74.2 %

Procedure:
2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl)phenyl)acetamide (25 g, 0.07338 mol) was dissolved in dimethyl formamide (75 ml). 1,8-diazabicyclo[5.4.0]undec-7-ene (17.5 ml, 0.11731 mol) and 4-amino phenol (9.6 g, 0.0879 mol) were added in one lot. The reaction mass was heated to 110-120° C. for 18-20 hours, cooled to room temperature and quenched in water (750 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. It was then dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (300 ml) at ambient temperature and filtered to give 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (18 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
2-Thiophenecarbonylchloride (2.04 g, 1.49 mL) was added to a solution of tert-butyl-1-piperazinecarboxylate (2.5 g, 13.4 mmol) and DMAP (20 mg) in pyridine (15 mL) at 0° C. under N2 atmosphere and stirred at room temperature for overnight. The mixture was poured into ice water, the precipitate was filtered, washed several times with water, and dried to yield white solids (3.5 g, 88%). Mp 76° C. 1H NMR (DMSO-d6): δ 1.42 (s, 12H), 3.40 (m, 4H), 3.61 (m, 4H), 7.12 (m, 1H), 7.43 (d, J=4.1 Hz, 1H), 7.77 (d, J=4.8 Hz, 1H). EIMS m/z 297 (M+1), 319 (M+23). Anal. (C14H20N2O3S) C, H, N.
Reaction SMILES: [CH2:1]([CH:5]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH:3]=[CH2:4].[OH-].[K+].CO.S(Cl)([Cl:29])=O>>[CH2:1]([CH:5]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([Cl:29])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCCC(Oc1ccc(C(=O)Cl)cc1)C1CCCCC1

Procedure:
65 g (0.2 mol) of the above tosyl ester were added to a solution of 36.5 g (0.24 mol) of potassium tert-butoxide dissolved in tert-butanol, and the mixture was warmed to reflux with stirring and stirred under reflux for 8.5 hours. After cooling, the mixture was hydrolyzed and extracted with methyl tert-butyl ether, and the organic phase was washed (twice with water), dried and evaporated. The residue was again partitioned between 2 N NaOH and methyl tert-butyl ether, and the purification procedure was repeated, giving 37 g (60%) of methyl 4-(but-3-enylcyclohexylmethoxy)benzoate. This ester was hydrolyzed in a conventional manner using KOH/methanol to give the free acid, which was reacted with thionyl chloride to give 4-(but-3-enylcyclohexylmethoxy)benzoyl chloride. 18 g (0.06 mol) of this acid chloride and 10.0 g (0.063 mol) of commercial 1,4-butanediol monomethacrylate (Polysciences, D-69208 Eppelheim) were dissolved in 15 ml of toluene, and a solution of 6.1 g (0.067 mol) of triethylamine dissolved in 40 ml of toluene was added dropwise over the course of 5 minutes. The mixture was stirred at 50° C. for 30 minutes, warmed to 80° C., and stirred at this temperature for a further 2 hours. The mixture was then cooled, and the precipitated amine hydrochloride was filtered off, washed with 0.5 N hydrochloric acid and then with water, dried and evaporated. The residue was purified on a silica gel column. The target product had an m.p. of 22-25° C.
Reaction SMILES: [Mg].II.Br[CH:5]=[C:6]([CH3:8])[CH3:7].[CH2:9]([Sn:13](Cl)([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12]>O1CCCC1.IC>[CH:5]([Sn:13]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][CH2:10][CH2:11][CH3:12])=[C:6]([CH3:8])[CH3:7]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)=CBr
Agent: II
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: CCCC[Sn](C=C(C)C)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A suspension of magnesium (2.64 g, 110 mmol) in dry tetrahydrofuran (60 mL) was treated with a small amount of iodine and then 1-bromo-2-methylpropene (13.5 g, 100 mmol) in tetrahydrofuran (30 mL) was added in several portions. The mixture was heated under reflux for 3 min. The mixture was cooled to 25° C. and then treated with iodomethane (0.2 mL, 3.0 mmol). The reaction mixture was stirred at 25° C. for 30 min and then heated under reflux for 2 h until all the magnesium was consumed. The mixture was cooled to 25° C. then treated with a solution of tributyltin chloride (27 mL, 100 mmol) in tetrahydrofuran (30 mL). The mixture was heated under reflux for 19 h and then cooled to 25° C. The solution was extracted with diethyl ether and a saturated aqueous ammonium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford isobutenyltri-n-butyltin (31.95 g) as a crude oil. The 1H-NMR data of the crude oil indicated 58% purity of the desired isobutenyltri-n-butyltin.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:23]([O-])=O)[CH:3]=1.[Sn](Cl)Cl>C(O)C>[NH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[C:4]([NH2:23])=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2ccc(Br)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cccc(Nc2ccc(Br)cc2N)c1
Yield: 99 %

Procedure:
A mixture of tert-butyl {3-[(4-bromo-2-nitrophenyl)amino]phenyl}carbamate (10.1 g, 24.7 mmol) and tin dichloride (24 g, 120 mmol, Aldrich, Cat. No. 208256) in ethanol (100 mL) was heated at 100° C. overnight. The solution was quenched with 1N NaOH aqueous solution, and then extracted with ethyl acetate twice. The combined organic phases were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired compound (6.8 g, 99%). LCMS (M+H)+: m/z=278.0.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]4[NH:39][N:38]=[N:37][N:24]=4)=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2cncnc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2cncnc2-c2nnn[nH]2)cc1

Procedure:
A solution of methyl 2-butyl-1-[p-(4-cyanopyrimidin-5-yl)benzyl]benzimidazole-7-carboxylate (0.18 g, 0.4 mmol) and trimethyltin azide (0.27 g, 1.3 mmol) in toluene (5 ml) was heated under reflux for 28 hours. After removal of the solvent by evaporation, the residue was purified by column chromatography on silica gel. Recrystallization from ethyl acetate-isopropyl ether afforded colorless powders (40 mg, 20%), m.p. 215°-220° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.Cl.[F:37][CH:38]([F:41])[CH2:39][NH2:40].C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:40][CH2:39][CH:38]([F:41])[F:37])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: NCC(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCC(F)F)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
140 mg (0.260 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), 61 mg (0.519 mmol) of 2,2-difluoroethylamine hydrochloride and 67 mg (0.519 mmol) of N,N-diisopropylethylamine were dissolved in 2 ml of tetrahydrofuran and stirred at room temperature overnight. Without further work-up, the reaction mixture was purified by preparative HPLC. 77 mg (yield: 51% of theory) of the target compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 12 h
Yield: 195246.5 %

Procedure:
To a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (500 g, 1.87 mol) in EtOH (2.2 L) stirred under nitrogen at 20° C. was added NaCN (93 g, 1.90 mmol) in one charge. The reaction mixture was stirred at 60° C. for 12 h. Then the solution was concentrated and distributed between DCM (2000 mL) and saturated NaHCO3 solution (1800 mL). Another batch was repeated using the same procedure. Then the two batches were combined. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated to provide 2-(4-bromo-2-fluorophenyl)acetonitrile (794 g, 99% yield): 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 3H), 3.72 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:41]=[CH:42][C:43]=1[NH:44][C:45]([NH:47][CH:48]1[CH2:50][CH2:49]1)=[O:46])[O:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)=[C:20]([C:23]#[N:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O>[Cl:8][C:9]1[CH:10]=[C:11]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[C:20]([C:23]#[N:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)[CH:41]=[CH:42][C:43]=1[NH:44][C:45]([NH:47][CH:48]1[CH2:49][CH2:50]1)=[O:46]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)c3cc2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OCCC1CCNCC1
Reaction time: 1 h
Yield: 100 %

Procedure:
After adding trifluoroacetic acid (3.0 ml) to tert-butyl 4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl)aminophenoxy)-6-cyano-7-quinolyl)oxy)ethyl)-1-piperidinecarboxylate (343 mg, 0.566 mmol) at room temperature, the mixture was stirred for 1 hour. The reaction solution was diluted with water (40 ml) while cooling in an ice water bath, and then sodium bicarbonate (4.0 g) was gradually added for neutralization and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was suspended in ethyl acetate and diluted with hexane, and the precipitated crystals were filtered out and blow-dried to obtain the title compound (286 mg, 0.566 mmol, quantitative) as light yellow crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21].[CH2:23]([C:25]1[CH:30]=[C:29]([CH2:31]Br)[CH:28]=[CH:27][N:26]=1)[CH3:24].O.C(#N)C>CN(C)C=O>[CH3:3][C:4]1([CH3:22])[N:8]([CH2:31][C:29]2[CH:28]=[CH:27][N:26]=[C:25]([CH2:23][CH3:24])[CH:30]=2)[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21]
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=O
Reactant: CCc1cc(CBr)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(CN2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(=O)C2(C)C)ccn1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
0.009 g of sodium hydride is added to a solution of 0.064 g of 5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 1 ml of anhydrous dimethylformamide, under an inert atmosphere of argon, at a temperature in the region of 20° C. Stirring is continued at this temperature for 30 minutes. A solution of 0.062 g of 2-ethyl-4-(bromomethyl)pyridine in 0.5 ml of anhydrous dimethylformamide is added, followed by addition of ice-cold water after reaction for 10 minutes. The reaction mixture is placed on a cartridge 27 mm in diameter packed with 25 g of octadecyl-grafted 40-60 μm silica conditioned successively with the mixture (water/acetonitrile)(5/95)(v/v) and then with the mixture (water/acetonitrile)(95/5)(v/v). The elution is performed with a mixture (water/acetonitrile) (95/5)(v/v) over 20 minutes, followed by a linear gradient of from 5% to 95% acetonitrile over 60 minutes, at a flow rate of 10 ml/minute. The fractions between 750 and 790 ml are concentrated under reduced pressure. 0.06 g of 5,5-dimethyl-1-(2-ethylpyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained, the characteristics of which product are as follows:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:24])(=[N:13][S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[O:12])=[CH:7][C:6]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Cl>O>[CH2:25]([C:6]1[CH:7]=[C:8]([S:11]([CH3:24])(=[N:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=2)(=[O:16])=[O:15])=[O:12])[CH:9]=[CH:10][C:5]=1[OH:4])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCc1cc(S(C)(=O)=NS(=O)(=O)c2ccc(C)cc2)ccc1OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCc1cc(S(C)(=O)=NS(=O)(=O)c2ccc(C)cc2)ccc1O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
A suspension of 0.8 g of the product of Step C, 30 ml of a saturated sodium carbonate solution and 15 ml of ethanol was stirred at 50° C. for 15 minutes and the solution was cooled in water. The mixture was acidified with concentrated hydrochloric acid and was extracted with ether. The decanted organic phase was evaporated to dryness to obtain 0.65 g of 2-hexyl-4-(S-methyl-N-tosyl-sulfonimidoyl)-phenol which after crystallization from an ether-petroleum ether mixture melted at 107°-109° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl-].[Li+].C(N(CC)CC)C.O.[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22]>C(#N)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(C)=O
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dichlorobenzaldehyde (17.5 g, 0.1 mol), triethyl phosphonoacetate (22.4 g, 0.12 mol), lithium chloride (5.1 g, 0.12 mol) and triethylamine (17 mL, 0.12 mol) in acetonitrile is stirred at room temperature for 1 hour and diluted with a water/ethyl acetate mixture. The organic phase is separated, washed with water dried over anhydrous Na2SO4 and concentrated in vacuo to give the title product as a yellow solid (42 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:13][C:14]([N:16]([CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17][C:18]([O:20]C)=[O:19])=[O:15])[C:6](=[O:12])[NH:7]2.[Li+].[OH-].O>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:13][C:14]([N:16]([CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:6](=[O:12])[NH:7]2
Reactant: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Cc1cc2c(C)ccnc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc2[nH]c(=O)c(CC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.5 %

Procedure:
To a solution of methyl N-((5-methyl-1,8-naphthyridin-2(1H)-on-3-yl)acetyl)-N-(2-(tert-butyloxycarbonyl)aminoethyl)glycinate (0.72 g, 1.70 mmol) in THF (10 mL) was added LiOH (aqueous, 2M) (2.0 mL). The resulting solution was stirred at rt. for 45 min. then additional water was added, the THF was evaporated in vacuo and the pH of the aqueous solution was adjusted to 3.0. The resulting precipitate was washed with water (2×10 mL), collected by centrifugation and dried in vacuo to yield the desired product (366 mg, 53%) as a white powder (mp 133-36° C.). 1H NMR (DMSO-d6; this compound exist as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 12.12 (s br, 1H), 8.33 (d, J=4.9 Hz, 1H), 8.00 (s, 1H), 7.09 (d, J=4.9 Hz, 1H), 6.92 (6.70) (m, 1H), 3.99 (4.26) (s, 2H), 3.62 (s, 2H), 3.45 (m, 2H+H2O), 3.17 (m, 2H), 2.53 (2.52) (s, 3H), 1.36 (1.34) (s, 9H) 13C NMR (DMSO-d6): δ 171.07 (171.31), 170.23 (170.54), 162.36, 155.80, 149.53, 149.27, 145.30, 132.67 (133.55), 129.35 (129.20), 119.92, 113.44, 78.01, 48.13, 47.33, 38.60 (38.36), 34.07, 28.27, 17.76. FAB− HRMS (m/z): 417.1798, calc. C20H26N4O6−H 417.1774.