Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)#[CH:20]>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:20]#[C:19][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(I)cc1
Reactant: C#Cc1ccc(C#C)cc1
Product: CCCCCCCCCCOc1ccccc1C#Cc1ccc(C#Cc2ccccc2OCCCCCCCCCC)cc1

Procedure:
Then, 1-decyloxy-4-iodobenzene and 1,4-diethynylbenzene are reacted to obtain 1,4-bis(decyloxyphenylethynyl)benzene as shown in the following reaction formula (38).
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH2:22])[CH2:20][CH3:21])=[CH:15][C:14]=1[CH3:23].[NH:24]1[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH:22][C:2]2[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH2:5][N:24]2[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]2)[CH2:20][CH3:21])=[CH:15][C:14]=1[CH3:23]
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1cccc(Br)c1F
Reactant: CC[C@@H](N)c1ccc(Cl)c(C)c1
Agent: Cl
Product: CC[C@@H](Nc1cccc(CN2CC(C(=O)O)C2)c1F)c1ccc(Cl)c(C)c1

Procedure:
The title compound was prepared according to Scheme 3 following a procedure analogous to steps 3 to 6 of Example 21 using 3-bromo-2-fluoro-benzaldehyde in step 3, (R)-1-(4-chloro-3-methyl-phenyl)-propylamine hydrochloride in step 4 and azetidine-3-carboxylic acid in step 6.
Reaction SMILES: [Cl:1][C:2]([Cl:11])=[CH:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](Cl)=[O:6].[C:12]([CH:14]([OH:28])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)#[N:13].N1C=CC=CC=1>C1C=CC=CC=1.C(OCC)C>[Cl:1][C:2]([Cl:11])=[CH:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([O:28][CH:14]([C:12]#[N:13])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)=[O:6]
Reactant: CC(C)C(C=C(Cl)Cl)C(=O)Cl
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)C(C=C(Cl)Cl)C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
In 20 ml of dry benzene were dissolved 2.0 g of α-(2,2-dichlorovinyl)isovaleric acid, followed by the addition of 6.0 g of thionyl chloride. The mixture was refluxed overnight. It was then distilled to remove the low-boiling fraction, whereby α-(2,2-dichlorovinyl)isovaleroyl chloride was obtained. This α-(2,2-dichlorovinyl)isovaleroyl chloride was dissolved in 25 ml of dry benzene, followed by the addition of 2.3 g of α-cyano-3-phenoxybenzyl alcohol and, then, 2.4 g of pyridine. The mixture was stirred at room temperature overnight. The resultant reaction mixture was diluted with diethyl ether, washed with water and dilute aqueous hydrogen chloride, dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. Column chromatography was carried out on the residue to obtain 3.2 g of α-cyano-3-phenoxybenzyl α-(2,2-dichlorovinyl)isovalerate (Compound [1]) which was shown to have the properties given below [yield: 78% based on α-(2,2-dichlorovinyl)isovaleric acid].
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]=2[C:8]=1[C:9]([O:11]CC)=[O:10].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]=2[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
A solution of the ester from Step 1 (0.8 g, 2.5 mmol) was dissolved in 40 mL of ethanol and 10 mL of tetrahydrofuran, treated with sodium hydroxide (2.5 N, 10 mL, 25 mmol) and stirred at room temperature for 16 hours. The reaction mixture was acidified with 1.0 N HCl, whereupon a solid formed that was isolated by filtration. The solid was washed with 20 mL of water to afford 0.7 g (95%) of the title compound as a yellow solid: mp 245.9–248.6° C. 1H NMR (acetone-d6/300 MHz) 8.57 (s, 1H), 8.28 (d, 1H, J=8.7 Hz), 8.03 (d, 1H, J=9.0 Hz), 7.93 (d, 1H, J=8.7), 7.67 (m, 1H), 7.50 (m, 1H), 7.28 (d, 1H, J=9.0), 5.96 (qH-F, 1H, J=7.2 Hz). FABHRMS m/z 295.0561 (M+H, Calc'd 295.0582). Anal. Calc'd for C15H9O3F3+3.31% H2O: C, 59.21; H, 3.35. Found: C, 59.17; H, 3.07.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(O)C.[CH3:8][N:9]([CH3:43])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[O:26][C:27](=[O:42])/[C:28](=[CH:30]/[C:31]4[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=4)/[N:29]=3)=[CH:21][CH:20]=2)=[CH:12][CH:11]=1>CO>[CH3:8][N:9]([CH3:43])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:29]/[C:28](/[C:27]([NH:1][CH2:2][CH2:3][OH:4])=[O:42])=[CH:30]\[C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:35][CH:36]=3)=[O:26])=[CH:21][CH:20]=2)=[CH:14][CH:15]=1
Reactant: CN(C)c1ccc(CCOc2ccc(C3=N/C(=C\c4ccc(OC(F)(F)F)cc4)C(=O)O3)cc2)cc1
Reactant: NCCO
Solvent: CCO
Solvent: CO
Product: CN(C)c1ccc(CCOc2ccc(C(=O)N/C(=C\c3ccc(OC(F)(F)F)cc3)C(=O)NCCO)cc2)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 63.6 %

Procedure:
2-Aminoethanol (57 μL, 0.944 mmol) was added to a solution of ethanol (0.5 mL) containing (4Z)-2-(4-{2-[4-(dimethylamino)phenyl]ethoxy}phenyl)-4-[4-(trifluoromethoxy)benzylidene]-1,3-oxazol-5(4H)-one (234 mg, 0.471 mmol) prepared in Example 23 (23c). The mixture was stirred at 60° C. for 2.5 hours, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol, 50:1, v/v) to give 167 mg of the title compound (white amorphous solid, yield: 64%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14](O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]1=[O:21])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>O1CCOCC1.C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14]([Cl:23])[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc[nH]2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccc[nH]2)c2ccc(Cl)cc21
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A suspension of 4.5 g of 1-acetyl-6-chloro-3-[1-hydroxy-1-(2-pyrrolyl)methylene]-2-indolinone and 3.4 g of phosphorus pentachloride in 50 ml of dioxane and 50 ml of toluene is stirred for 3 hours at 90° C. Then the solvent is distilled off and the residue is purified by chromatography on silica gel (eluant: toluene).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44].O>CN(C)C=O>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: CN(C)C(=O)CCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Rac-cis-(3,5-Bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone (200 mg, 0.41 mmol) was dissolved in N,N-dimethylforamide (5 mL). Potassium carbonate (171 mg, 1.24 mmol) and 2-chloro-N,N-dimethylacetamide (0.042 mL, 0.41 mmol) were added and the reaction mixture was stirred at room temperature overnight. Water (50 mL) was added and the mixture was extracted twice with 100 mL ethyl acetate. Organic phases were pooled, dried with magnesium sulfate and evaporated. Chromatography on silica gel with methylen chloride/methanol/triethyl amine 90:10:1 gave the desired product (200 mg, 85%) as an off-white solid, MS: m/e=571.1 (M+H+).
Reaction SMILES: C(OC([NH:11][C@H:12]([C@@H:20]([OH:41])[CH2:21][C@@H:22]([NH:30]C(OCC1C=CC=CC=1)=O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O1CCOCC1.O>[CH:12]([NH2:11])([CH3:20])[CH3:13].[NH2:11][C@H:12]([C@@H:20]([OH:41])[CH2:21][C@@H:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Yield: 122.7 %

Procedure:
A suspension of 32 g of the crude resultant compound of Example 1 E and 55.5 g (176 mmol) of barium hydroxide octahydrate in 400 ml of 1,4-dioxane and 400 ml of water was heated at reflux for 4 h. The resulting mixture was filtered, and the residue was rinsed with dioxane. The combined filtrates were concentrated to a volume of approximately 200 ml and extracted with four 400 ml portions of chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using first 2% isopropylamine in chloroform and then 2% isopropylamine/2% methanol in chloroform to provide 10.1 g (81%) of the pure desired compound as a white solid. 1H NMR (CDCl3) δ 1.54 (dt, J=14, 10 Hz, 1H), 1.67 (dt, J=14, 3 Hz, 1H), 2.50 (dd, J=13, 8 Hz, 1H), 2.58 (dd, J=13,8Hz, 1H), 2.8 (m, 2H), 2.91 (dd, J=13,5 Hz, 1H), 3.10 (m, 1H), 3.72 (ddd, J=11,3,2 Hz, 1H), 7.1-7.4 (m, 10H). Mass spectrum: (M+H)+ =285.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:8]1[NH:13][CH:12]=[N:11][C:10](=O)[C:9]=1[F:15])[CH3:7].C(N(CC)CC)C.[ClH:23]>C(Cl)Cl>[Cl:23][C:10]1[C:9]([F:15])=[C:8]([CH2:6][CH3:7])[N:13]=[CH:12][N:11]=1
Reactant: Cl
Reactant: CCc1[nH]cnc(=O)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ncnc(Cl)c1F
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (0.787 mL, 8.44 mmol) was added slowly over 10 min to a mixture of 6-ethyl-5-fluoropyrimidin-4(1H)-one (1 g, 7.04 mmol) (Apollo Scientific) and triethylamine (0.981 mL, 7.04 mmol) in DCM (15 mL), keeping the reaction temperature below 40° C. The mixture was then heated to reflux for 5 hrs then cooled to room temperature. The reaction mixture was then slowly poured into aqueous HCl (4M, 20 mL), keeping the temp below 20° C. The organic layer was collected and the aqueous layer was further extracted with DCM (20 mL). The organic layers were combined then washed with water (20 mL), dried (MgSO4) filtered and the solvent was removed to give the title compound as a colourless oil (1 g).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[CH3:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([NH2:37])[CH:34]=[CH:33][C:31]=2[N:32]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:37]([C:35]3[CH:34]=[CH:33][C:31]4[N:32]=[C:28]([CH3:27])[S:29][C:30]=4[CH:36]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Cc1nc2ccc(N)cc2s1
Product: Cc1nc2ccc(N3CCC4(CCN(S(=O)(=O)c5ccccc5Cl)CC4)C3=O)cc2s1

Procedure:
Light yellow crystalline solid. MS (ESI): 476.1 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 2-methyl-benzothiazol-6-ylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1F.[NH2:13][C@H:14]([C:18]([O-:20])=[O:19])[CH:15]([CH3:17])[CH3:16].[K+].S1(CCCC1)(=O)=O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[NH:13][CH:14]([CH:15]([CH3:17])[CH3:16])[C:18]([OH:20])=[O:19]
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: CC(C)[C@H](N)C(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Temperature: 125 °C
Yield: 96 %

Procedure:
A mixture of 10 parts of 3-chloro-4-fluorobenzotrifluoride, 10 parts of potassium valinate and 50 parts of sulfolane was heated and maintained at about 125° C. for about 17 hours, with mixing. The mixture was then cooled to room temperature, diluted with water and acidified with hydrochloric acid to a pH of 1.0. The aqueous layer was extracted with diethyl ether. The ether layers were washed with water, then dried and concentrated by evaporation to yield 9.6 parts of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (96% purity); a yield of about 65% based on the 3-chloro-4-fluorobenzotrifluoride starting material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:9][CH2:10][CH2:11][CH3:12])[O:16][CH2:15][CH2:14][O:13]2)=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CCCCC(=O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCC1(c2ccc(Br)cc2)OCCO1
Yield: 91.5 %

Procedure:
To a solution of 4′-bromovalerophenone (2.41 g, 10 mmol) in benzene (60 ml) was added ethylene glycol (2.0 ml, 36 mmol), p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) and the mixture refluxed under nitrogen in a Dean-Stark apparatus for 16 h. The reaction mixture was washed with sodium bicarbonate solution (5%, 50 ml), brine (1×50 ml), dried (Na2SO4) and evaporated to give 2-(4-bromophenyl)-2-butyl-1,3-dioxolane (11) as a clear oil (2.61 g, 92%). 1H nmr (CDCl3, 300 MHz) 0.88, t (6.9 Hz), H4″; 1.2-1.4, m, H2″,3″; 1.88, m, H1″; 3.7-3.8, m, CH2O; 4.0-4.1, m, CH2O; 7.34, d (8.4 Hz), H2′,6′; 7.49, d (8.4 Hz), H3′,5′. ESI (+ve) MS m/z 285/287 (M+H, 8%).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1.[C:32]([O-:40])(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.[Cs+].[I-].[Na+].O>C(#N)C>[C:28]([N:5]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)[C:4]([O:3][CH2:2][O:40][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)=[O:31])(=[O:30])[CH3:29]
Reactant: O=C([O-])c1ccncc1
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)c1ccncc1
Temperature: 25 °C
Yield: 80 %

Procedure:
(R)-acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid chloromethyl ester (10) (0.40 g, 0.84 mmol), cesium isonicotinate (0.33 g, 1.301 mmol) and sodium iodide (0.13 g, 0.86 mmol) in acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 80%. 1H NMR (400 MHz, DMSO-d6): δ 8.78 (d, 2H), 7.82 (d, 2H), 7.36 (d, 1H), 7.30 (t, 1H), 7.18 (d, 1H), 6.02 (dd, 2H), 4.76-4.70 (m, 1H), 4.10-4.05 (m, 2H), 3.89-3.85 (m, 1H), 3.77-3.74 (m, 1H), 3.35-3.26 (m, partially obscured by water, 2H), 3.19-3.11 (m, 1H), 3.07-3.04 (m, 2H), 2.43 (d, partially obscured by DMSO, 3H), 2.11 (q, 2H), 2.01-1.97 (m, 2H); MS-APCI (m/z+): 341, 564.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=C(C3C=CC=CC=3)[C:3]=12.[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.[CH3:32]NN>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:32])[N:15]=[C:26]([C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[CH3:23])[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: Cc1ccccc1C=O
Reactant: CNN
Product: Cc1ccccc1-c1nn(C)c2nnc(-c3ccccc3)c(Cl)c12

Procedure:
Compound 20 was synthesised following similar procedures outlined in Example 22 (Compound 9), using 2-methylbenzaldehyde instead of benzaldehyde in Step 1 and methyl hydrazine instead of hydrazine hydrate in Step 3.
Reaction SMILES: [NH2:1][C:2](=[N:21][OH:22])[C:3]1[CH:4]=[CH:5][C:6]([F:20])=[C:7]([CH:19]=1)[CH2:8][N:9]([CH3:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][C:27]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41]>>[F:20][C:6]1[CH:5]=[CH:4][C:3]([C:2]2[N:1]=[C:32]([C:30]3[CH:29]=[CH:28][C:27]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[C:26]([CH2:25][O:24][CH3:23])[CH:31]=3)[O:22][N:21]=2)=[CH:19][C:7]=1[CH2:8][N:9]([CH3:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(F)c(CN(C)CC(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 60 (256.87 mg; 0.83 mmol) and Intermediate 28 (192.22 mg; 0.75 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a slightly yellow oil. 1H NMR (CDCl3) δ 8.42 (d, J=1.4 Hz, 1H), 8.27 (d, J=5.8 Hz, 1H), 8.19-8.09 (m, 2H), 7.36-7.12 (m, 6H), 4.23 (s, 2H), 3.92 (s, 2H), 3.33 (s, 3H), 3.29 (s, 2H), 2.48 (s, 3H), 2.08 (s, 3H), 1.51 (s, 9H). LC/MS (Method B): 532.3 (M+H)+. HPLC (Method A) Rt 4.85 min (Purity: 98.6%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:11]([O:13]CC)=O)=[CH:4][C:3]=1[O:22][CH3:23].CCCCCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:22][CH3:23])[NH:8][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:10][C:11]2=[O:13]
Reactant: CCOC(=O)C=C(Nc1ccc(Br)c(OC)c1)c1ccccc1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2[nH]c(-c3ccccc3)cc(=O)c2cc1Br
Temperature: 25 °C
Yield: 88.5 %

Procedure:
DOWTHERM A (450 mL) was heated to reflux (˜300 C). A mixture of the product from step 2 (49 g, 130 mmol) in DOWTHERM A (50 mL) was added to the heated DOWTHERM A solution portionwise. The mixture was stirred at reflux for 30 min after the addition was complete. The mixture was cooled RT, and hexane (400 mL) was added. The mixture was stirred for 30 min and filtered, and the solids were washed with hexane to give the title compound (38 g, 88% yield). LRMS (M+H)+ Calcd.: 330.0; found 330.2.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]3[CH2:28][O:27][CH2:26][CH:25]3[C:29]([OH:31])=O)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:32][OH:33]>>[OH:33][NH:32][C:29]([C@H:25]1[C@@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[CH2:28][O:27][CH2:26]1)=[O:31]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3COCC3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3COC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 11 %

Procedure:
According to the procedure of Example 24, Step 3, 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid (0.6 g, 1.35 mmol) and hydroxylamine afforded (3S,4R)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide as an amorphous white solid (0.07 g, 11%) after HPLC purification, eluting with acetonitrile:water. MS: 458 (M+H)+
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[O:10][C:9](=[O:16])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:18]1[CH:36]=[CH:35][C:21]([C:22]([NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.C(Cl)Cl.[Cu]I>[O:16]=[C:9]1[N:8]([C:18]2[CH:36]=[CH:35][C:21]([C:22]([NH:24][C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)=[O:23])=[CH:20][CH:19]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10]1
Reactant: O=C1NC(c2ccccc2)C2(CCCC2)O1
Reactant: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1cccc2cccnc12)c1ccc(N2C(=O)OC3(CCCC3)C2c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 11 %

Procedure:
To a 50 mL dried round bottom flask containing a degassed solution of 4-phenyl-1-oxa-3-azaspiro[4.4]nonan-2-one (1 eq., 1.73 mmol) and 4-iodo-N-(quinolin-8-yl)benzamide (1.2 eq.) in DMF (15 mL), potassium carbonate (2.5 eq.) and trans (N,N)-dimethyl cyclohexanediamine (0.5 eq.) was added CuI (0.1 eq). The resulting mixture was stirred at 120° C. for 15 hours. Reaction progress was monitored by TLC (TLC eluent: 10% MeOH in DCM). The reaction mixture was cooled and poured into crushed ice (5 g). The solid thus obtained was filtered, washed with water (25 mL) and dissolved in DCM. The DCM solution was then washed with water (100 mL), washed brine (50 mL) and dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography using silica gel and DCM as eluting solvent to yield (R+S) 4-(2-oxo-4-phenyl-1-oxa-3-azaspiro[4.4]nonan-3-yl)-N-(quinolin-8-yl)benzamide (90 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 10.55 (s, 1H), 8.94 (d, J=4 Hz, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.75-7.63 (m, 5H), 7.39-7.32 (m, 5H), 5.75 (s, 1H), 2.10-2.20 (m, 2H), 1.50-1.78 (s, 4H), 1.30-1.40 (m, 1H), 1.10-1.20 (m, 1H). m/z (ESI) 464.3 (M+H)+.