Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]2[O:21]C(=O)[NH:19][C:16]2=[N:17][CH:18]=1.[OH-].[Na+]>>[Br:12][C:13]1[CH:14]=[C:15]([OH:21])[C:16]([NH:19][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:17][CH:18]=1
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)Nc2ncc(Br)cc2O)cc1

Procedure:
With 4-methylbenzenesulfonyl chloride, 6-bromo-[1,3]-oxazolo[4,5-b]pyridin-2(3H)-one (described in Heterocycles, 41, 2799 (1995)) was allowed to react. Then, with an aqueous solution of sodium hydroxide, the mixture was hydrolyzed to give the title compound having the following physical data.
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:6]1.[F:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][N:27]([CH:28]([CH3:30])[CH3:29])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:4][CH:3]=[C:2]([CH3:1])[CH3:19])[CH:6]=1)=[O:25]
Reactant: CC(C)=CCn1cc(C=CC(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCn1cc(/C=C/C(=O)N(NC(=O)c2cccc(F)c2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acrylic acid (200.0 mg, 0.78 mmol), 3-fluoro-N′-isopropylbenzohydrazide (229.6 mg, 1.17 mmol) and HATU (444.9 mg, 1.17 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.2 ml, 1.17 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (50% EtOAc) and dried so that yellow (E)-3-fluoro-N′-isopropyl-N′-(3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acroyl)benzohydrazide was obtained (286 mg, 88.2%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C@@H:24]([CH3:28])[C:25]([OH:27])=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([O:23][C@@H:24]([CH3:28])[C:25]([NH2:30])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(=O)O)cc1OCC2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.3 %

Procedure:
To a solution of (S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionic acid (115 mg, 0.28 mmol) in DMF (3 mL) was added HATU (128 mg, 0.34 mmol), ammonium chloride (23 mg, 0.42 mmol) and triethylamine (67 μL, 0.42 mmol) and the reaction mixture stirred at room temperature (RT) for 5 hours. Further quantities of HATU (106 mg, 0.28 mmol), ammonium chloride (15 mg, 0.28 mmol) and triethylamine (21 μL, 0.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (C-18 column, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) to yield 426 as a white solid (68 mg, 58%). LCMS: RT=3.07 min, [M+H]+=384; 1H NMR (400 MHz, d6-DMSO) 9.05 (1H, s), 7.87 (1H,$), 7.86 (1H, s), 7.38 (1H, s), 7.05 (1H, s), 6.41 (1H, s), 5.87 (1H, sept, J=6.6 Hz), 5.17 (1H, q, J=6.9 Hz), 4.59-4.43 (4H, m), 1.47-1.37 (9H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22].[NH4+].[Cl-]>C(Cl)Cl>[OH:13][C:10]([C:3]1[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:21](=[O:23])[CH3:22])([CH3:11])[CH3:12]
Reactant: CC(=O)Cl
Reactant: COc1cccc(N)c1C(C)(C)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(NC(C)=O)c1C(C)(C)O
Temperature: 0 °C

Procedure:
2-(2-Amino-6-methoxyphenyl)propan-2-ol (Intermediate 199, 500 mg, 2.76 mmol) was dissolved in DCM (10 mL) and triethylamine (0.770 ml, 5.52 mmol) was added. The solution was cooled to 0° C. and treated with acetyl chloride (0.2 ml, 2.76 mmol) in a drop wise fashion. At the end of the addition, complete conversion was reached. The mixture was treated with an aqueous saturated solution of NH4Cl, two phases were separated and the organic layer was washed with an aqueous saturated solution of NaHCO3 and brine, then dried over Na2SO4 and evaporated to dryness. The crude was purified by re-slurry in tert-butyl methyl ether isolating 490 mg of the title compound as white solid.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C@@H:7]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][OH:9].[OH-].[Na+].C1COCC1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH2:12]([O:11][CH2:10][C@@H:7]1[NH:6][C:3](=[O:4])[CH2:2][O:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@H](CO)COCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1COC[C@H](COCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (0.242 mL) was added to a mixed solution of (R)-(+)-2-amino-3-benzyloxy-1-propanol (500 g) in toluene (7 mL) and a 2 N sodium hydroxide solution (7 mL) under ice-cooling. The reaction solution was stirred at room temperature for one hour. Then, THF and brine were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Sodium iodide (82.7 mg) and potassium tert-butoxide (681 mg) were added to a solution of the resulting residue in THF (15 mL) under ice-cooling. The reaction solution was stirred at room temperature for one hour. Then, a saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: heptane-ethyl acetate system) to obtain 387 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH2:15]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH3:17]>>[O:5]=[C:4]1[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[S:11][C:12]([N:18]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH3:17])=[N:13]1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: N#C[S-]
Reactant: CCCNc1ccc(C(=O)OCC)cc1
Agent: [NH4+]
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1nc(=O)c2cccnc2s1
Yield: 86.9 %

Procedure:
The reaction procedure of Example 57 was followed except that 230 mg of 2-chloronicotinoyl chloride, 100 mg of ammonium thiocyanate and 270 mg of ethyl 4-(propylamino)benzoate were used. As a result, 418 mg of ethyl 4-[N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)-N-propylamino)benzoate was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:14])[N:9]([CH3:13])[S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:13][N:9]1[C:8](=[O:14])[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([C:15]([Cl:20])=[O:17])[C:2]=2[CH3:1])[S:10]1(=[O:12])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc2c1C(=O)N(C)S2(=O)=O
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Cl)ccc2c1C(=O)N(C)S2(=O)=O
Temperature: 80 °C
Yield: 74 %

Procedure:
3.8 g (14.9 mmol) of 4,N-dimethyl-1,1,3-trioxo-2,3-dihydro-1λ6 benz[d]isothiazole-5-carboxylic acid are suspended in 100 ml of toluene, and the mixture is heated to 80° C. and 3.5 g (29.8 mmol) of thionyl chloride are added dropwise. After refluxing for two hours, the solution is decanted hot and the reaction mixture is concentrated on a rotary evaporator. Yield: 74% of theory, m.p.: 149°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH2:28].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:28][C:24]2[S:23][CH:27]=[CH:26][N:25]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Reaction time: 2 h
Yield: 61.5 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 93 mg, 0.27 mmol), thiazol-2-ylamine (27 mg, 0.27 mmol) and N,N-diisopropylethylamine (141 μL, 0.82 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-thiazol-2-yl-acetamide (71 mg, 62%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H18ClN3O4S2 [M+] 427.04, found 428 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 4.96 (m, 1 H, OCH), 7.05 (d, J=3.5 Hz, 1 H, Ar), 7.52 (d, J=3.5 Hz, 1 H, Ar), 7.60 (dd, Jo=8.2, Jm=1.2 Hz, 1 H, Ar), 7.71 (d, Jm=1.2 Hz, 1 H, Ar), 8.20 (d, Jo=8.2 Hz, 1 H, Ar), 10.20 (s, 1 H, NH).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][C:36](O)=[O:37])[CH:29]=1.C(Cl)CCl>C1COCC1>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][C:36]([N:11]2[CH2:10][CH2:9][N:8]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:21][CH:22]=3)(=[O:15])=[O:16])[CH2:13][CH2:12]2)=[O:37])[CH:29]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)cc1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)CCc3cccnc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.8 %

Procedure:
Triethylamine (0.28 ml, 2.04 mmol) was added in one portion to a stirred solution of N-[4-(piperazine-1-sulfonyl)-phenyl]-acrylamide (0.2 g, 0.68 mmol) and 3-pyridine propionic acid (0.1 g, 0.68 mmol) in THF (5 ml). The mixture was stirred at room temperature for 5 minutes before EDC (0.26 g, 1.36 mmol) was added in one portion and the resulting mixture and stirred at room temperature under a nitrogen atmosphere for 18 hours. The crude reaction mixture was concentrated under vacuum and the resulting residue dissolved in DCM (20 ml), washed with water (20 ml), dried (MgSO4), filtered and concentrated under vacuum. The crude product was purified by Prep HPLC to give the title compound (0.046 g, 15% yield) as a white powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[N:7][C:8]=2[CH3:12])[N:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CN(C)C=O.O.C(O[Pd]OC(=O)C)(=O)C>[CH3:12][C:8]1[N:7]=[CH:6][C:5]([CH3:13])=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2](/[CH:16]=[CH:15]/[C:14]([O:18][CH2:19][CH3:20])=[O:17])=[N:3]2
Reactant: Cc1ncc(C)c2nc(Br)ccc12
Reactant: C=CC(=O)OCC
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(C)ncc(C)c2n1
Temperature: 150 °C
Yield: 86.7 %

Procedure:
A mixture of 2-bromo-5,8-dimethyl-1,6-naphthyridine (0.63 g, 2.7 mmol), ethyl acrylate (0.53 g, 5.4 mmol), diacetoxypalladium (121 mg, 0.5 mmol), PPh3 (0.35 g, 1.4 mmol), and NEt3 (0.82 g, 8.1 mmol) in N,N-dimethylformamide (5 mL) was heated in a microwave reactor at 150° C. for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with saturated sodium chloride solution (50 mL×3), dried with sodium sulfate and concentrated to give 0.6 g of the crude product as a yellow solid, which was used for the next step without further purification. MS (ESI): m/z 257.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][OH:29])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:33][CH3:34]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH2:33][CH3:34])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of (R)-1-(4-fluorophenyl)-4a-hydroxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester (0.25 g) in tetrahydrofuran (2.5 mL) under argon at room temperature was treated sequentially with sodium hydride (0.072 g, 60% dispersion in mineral oil) and iodoethane (0.15 mL), and the resulting mixture was stirred at 50° C. for 2 hour. The solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (9:1 by volume), to afford the title compound as an amber gum (0.21 g). LCMS (Method E): 428 (M+H)+, Retention time 4.7 minutes.
Reaction SMILES: [N+:1]([N:3]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[C-:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH:27]=[O:28].[O:33]=[C:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH2:45][C:46]([OH:48])=O)[CH:40]=2)[NH:35]1>ClCCl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]([OH:28])[C:2]2[O:48][C:46]([CH2:45][O:44][C:39]3[CH:40]=[C:41]4[C:36](=[CH:37][CH:38]=3)[NH:35][C:34](=[O:33])[CH2:43][CH2:42]4)=[N:3][N:1]=2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: [C-]#[N+]N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)COc1ccc2c(c1)CCC(=O)N2
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: O=C1CCc2cc(OCc3nnc(C(O)c4ccc(Cl)c(Cl)c4)o3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
A mixture of N-isocyaniminotriphenylphosphorane (0.204 g, 0.678 mmol), 3,4-dichlorobenzaldhyde (0.158 g, 2.712 mmol), and 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetic acid (0.150 g, 0.678 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight. Solvent was removed under vacuum. The crude product was recystallised in ACN/Ethanol to afford 6-((5-((3,4-dichlorophenyl)(hydroxy)methyl)-1,3,4-oxadiazol-2-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (40 mg, 14%) as an off white solid. 1H NMR: 400 MHZ, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.82 (t, J=8.00 Hz, 2H), 5.32 (s, 2H), 6.11 (d, J=5.60 Hz, 1H), 6.77 (d, J=8.40 Hz, 1H), 6.82 (dd, J=2.40, 8.60 Hz, 1H), 6.88 (s, 1H), 7.00 (d, J=5.60 Hz, 1H), 7.45 (dd, J=1.60, 8.40 Hz, 1H), 7.67 (d, J=8.40 Hz, 1H), 7.72 (d, J=1.60 Hz, 1H), 9.95 (s, 1H). LCMS: RT 1.76 min. LCMS (ES-API), m/z 422.0 (M+H).
Reaction SMILES: [OH-].[K+].[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:19]([C:22]([CH3:24])=[O:23])([CH3:21])[CH3:20].C(O)(=O)C>CO.O>[F:18][C:17]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:24][C:22](=[O:23])[CH:19]([CH3:21])[CH3:20])=[CH:11][C:10]=1[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C(=O)C=Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.1 ml of 15% strength aqueous potassium hydroxide solution are added to 64.8 g (0.3 mol) of 3-phenoxy-4fluorobenzaldehyde and 51.6 g (0.6 mol) of methyl isopropyl ketone in 90 ml of methanol and the mixture is stirred overnight at room temperature. The mixture is neutralized using 1.95 ml of glacial acetic acid, diluted using 300 ml of water and extracted a number of times using ether. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 1:9).
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(Cl)(=[O:20])C1C=CC=CC=1.O>N1C=CC=CC=1.C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[OH:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC1(C)Oc2c(O)cccc2C1=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
7-Hydroxy-2,3-dihydro-2,2-dimethylbenzofurane is dissolved in 100 ml pyridine. 0.5 mol benzoyl chloride is added dropwise at 0° C. within 4 h. Subsequently it is stirred for 10 h at room temperature. It is poured onto 200 ml ice water and aspirated. The residue is washed with 500 ml 2 M hydrochloric acid and then with 1000 ml water and dried in air. A solution of 0.906 mol chromium trioxide in 370 ml glacial acetic acid is added dropwise to a solution of this crude product (0.45 mol) in 600 ml glacial acetic acid in such a way that the temperature of the mixture does not exceed 20° C. After the dropwise addition is completed it is stirred for a further 1 hour at 40° C. and subsequently poured onto 2 l water. It is suction filtered. The residue is washed with 1 l water and recrystallized from ethanol/water 3:1. The benzoyl compound is fed into 400 ml 10% ethanolic potassium hydroxide solution and the mixture is heated for 1 hour to 70° C. It is admixed with 3 l water and suction filtered. The residue is recrystallized from 2 l water.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[N:27]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=O)[CH2:29][CH2:28]1.[F:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>O1CCCC1.O>[F:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:33]([CH:30]2[CH2:29][CH2:28][N:27]([C:20]3[C:19]4[C:24](=[CH:25][CH:26]=[C:17]([Br:16])[CH:18]=4)[N:23]=[CH:22][CH:21]=3)[CH2:32][CH2:31]2)=[O:35])=[CH:39][CH:38]=1
Reactant: O=C(O)C1CCN(c2ccnc3ccc(Br)cc23)CC1
Reactant: Nc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)C1CCN(c2ccnc3ccc(Br)cc23)CC1

Procedure:
0.34 mL triethylamine and 0.13 mL isobutyl chloroformate were added to a solution of 50 mg 1-(6-bromo-4-quinolyl)-4-piperidinecarboxylic acid in tetrahydrofuran (5 mL) with stirring under ice-cooling, and the mixture was stirred for 0.5 hour in a stream of nitrogen. To this solution was added a solution of 1.5 mL 4-fluoroaniline in tetrahydrofuran (8 mL), and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction mixture which was then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 73 mg of the title compound as pale purple crystals.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([N:12]1[CH2:17][CH:16]2[CH2:18][CH:13]1[CH2:14][NH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]1[CH2:17][CH:16]2[CH2:18][CH:13]1[CH2:14][N:15]2[CH2:3][CH2:2][C:1]#[N:4])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C=CC#N
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Solvent: Cc1ccccc1
Product: N#CCCN1CC2CC1CN2Cc1ccccc1
Yield: 89.2 %

Procedure:
Freshly distilled acrylonitrile (2.5 g) is added to a solution of 3 g of 2-benzyl-2,5-diazabicyclo [2.2.1]heptane in 40 mL of anhydrous toluene and refluxed with vigorous stirring. The solution was cooled, filtered and evaporated. Bulb tube distillation (boiling point: 120°-130° C. at 0.01 mbar) resulted in 3.43 g of 142 as a colorless oil (88% of the theoretical yield).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:17]([N:24]1[CH2:29][CH2:28][N:27]([C:14]([C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:16])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 74.3 %

Procedure:
A solution of (S)-(−)-1-Boc-2-piperidine carboxylic acid 1 g (4.27 mmol), 1-benzylpiperazine 0.77 g (4.27 mmol), EDC 1.64 g (8.54 mmol) and catalytic amount of 4-(dimethylamino)pyridine in methylene chloride (50 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 1.23 g of desired product in 74.5% yield.