Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2][CH3:3].N1C2C(=CC=CC=2)C(=O)[C:16]1=O.BrCCCC>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2][CH2:3][CH3:16]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CCCCBr
Product: CCCCN1C(=O)C(=O)c2ccccc21

Procedure:
Was made in an analogous fashion to 1-propylindoline-2,3-dione by reacting commercially available isatin (purchased from Fisher Scientific) with 1-bromo-butane (purchased from Fisher Scientific). 1H-NMR δ 7.68 (m, 2H), 7.11 (dd, 1H), 6.90 (d, 1H), 3.72 (t, 2H), 1.65 (q, 2H), 1.41 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of DMF (50 mL) was added 1-bromo-2-nitro-4-chloro-benzene (5.0 g, 21.1 mmol), phenol (1.9 g, 21.1 mmol), and Na2CO3 (2.3 g, 21.1 mmol). The solution was heated to 85° C. and stirred overnight. The reaction was poured into water and extracted with EtOAc. Washed with water and dried over Na2SO4, filtered and concentrated under vacuum giving a yellow oil that was purified by silica gel column chromatography eluting with Hexanes:Ethyl Acetate (90:10) to give 4-chloro-2-nitro-1-phenoxy-benzene (3.8 g, 74%). 4-Chloro-2-nitro-1-phenoxy-benzene (13 g, 52.1 mmol) was reacted with SnCl2 (49.3 g, 260 mmol) following the procedure from Example 7f giving 5-chloro-2-phenoxy-phenylamine as a white solid 9.0 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH:31]=O)=[CH:26][CH:25]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:40])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:41][CH:42]1[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:44]2[CH2:45][CH2:46][CH2:47][CH:42]([OH:41])[CH2:43]2)=[CH:26][CH:25]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:40])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Reactant: OC1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(CN4CCCC(O)C4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 34.3 %

Procedure:
In a similar manner to Step 2 of Example 147, 4-[3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (104 mg, 0.188 mmol) was dissolved in acetonitrile (5.2 mL), and the solution was treated with 3-hydroxypiperidine (76.0 mg, 0.752 mmol), acetic acid (0.215 mL, 3.76 mmol) and sodium triacetoxyborohydride (160 mg, 0.752 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-[3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(3-hydroxypiperidinomethyl)indol-2-yl]isoindolinone (40.9 mg, yield 34%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH2:18]([C:22]1([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21].FC(F)(F)S(O)(=O)=O>ClCCl>[CH2:18]([C:22]1([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1(N2CCCC2)CCC(=O)CC1
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC1(N2CCCC2)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
3-(2-pyridin-4-ylethyl)-1H-indole (667 mg, 3 mmol, synthesis cf. WO2008009415, indole unit Ind-14) together with 4-butyl-4-(pyrrolidin-1-yl)cyclohexanone (671 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-14) was dissolved in abs. dichloromethane (45 ml) and mixed with trifluoromethane sulphonic acid (0.613 ml, 6.9 mmol). The batch was stirred for 64 h at RT, and a brown oil separated out. For work up the reaction solution was mixed with 1N NaOH (30 ml) and methanol (10 ml). The mixture was stirred a further 60 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.35 g) was purified by column chromatography [silica gel 60 (90 g); ethyl acetate/methanol (1:1 (2400 ml)].
Reaction SMILES: NCC1C=NC=CC=1.Cl.Cl.[CH3:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][NH2:18])[N:16]=1.[F:19][C:20]1[CH:41]=[CH:40][C:23]([CH2:24][N:25]2[C:29](=[O:30])[N:28]([C:31]3[S:35][C:34]([C:36](O)=[O:37])=[C:33]([CH3:39])[CH:32]=3)[CH:27]=[N:26]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:41]=[CH:40][C:23]([CH2:24][N:25]2[C:29](=[O:30])[N:28]([C:31]3[S:35][C:34]([C:36]([NH:18][CH2:17][C:15]4[N:16]=[C:12]([CH3:11])[S:13][CH:14]=4)=[O:37])=[C:33]([CH3:39])[CH:32]=3)[CH:27]=[N:26]2)=[CH:22][CH:21]=1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(CN)cs1
Agent: Cl
Agent: NCc1cccnc1
Product: Cc1nc(CNC(=O)c2sc(-n3cnn(Cc4ccc(F)cc4)c3=O)cc2C)cs1
Yield: 80 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 3-(aminomethyl)pyridine with 1-(2-methyl-1,3-thiazol-4-yl)methylamine dihydrochloride to react with 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid, the title compound was obtained as a colorless solid in 80% yield: mp 148-150° C.; 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.40-7.33 (in, 2H), 7.07-6.99 (in, 2H), 7.03 (s, 1H), 6.89 (s, 1H), 6.50 (t, J=4.9 Hz, 1H), 4.96 (s, 2H), 4.62 (d, J=4.9 Hz, 2H), 2.69 (s, 3H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.7, 162.6 (d, JC-F=247.1 Hz), 162.2, 151.8, 150.4, 140.0, 134.5, 132.4, 131.2 (d, JC-F=3.3 Hz), 130.3 (d, JC-F=8.3 Hz), 126.1, 120.4, 115.7 (d, JC-F=21.7 Hz), 115.0, 48.9, 40.0, 19.1, 16.0; MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: Br[C:2](Cl)(Cl)[C:3]([Br:6])(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([C@@H](O)C)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.CCCCCC>C1(C)C=CC=CC=1>[Br:6][C@@H:3]([C:32]1[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:30]([C:29]([F:28])([F:44])[F:43])[CH:31]=1)[CH3:2]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
Under an argon atmosphere, 1,2-dibromo-1,1,2,2-tetrachloroethane (7.57 g, 23.2 mmol) was dissolved in toluene (12.5 mL), the solution was added with triphenylphosphine (6.1 g, 23.2 mmol) at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was added dropwise with a solution of (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (5.0 g, 19.4 mmol, >99.5% ee) in toluene (12.5 mL) at 0° C. over 10 minutes or more, and then the mixture was warmed to room temperature, and stirred at the same temperature for 1 hour. The reaction mixture was added with n-hexane (25 mL), and the mixture was filtered through Celite. The filtrate was washed successively with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was distilled under reduced pressure (56° C., 0.7 mmHg) to obtain 5.52 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12]([NH2:13])=[N:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.[I:16]I>CO.ClCCl>[I:16][C:14]1[C:12]([NH2:13])=[N:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:1]1[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Reactant: II
Solvent: CO
Solvent: ClCCl
Product: Nc1nc(=O)n([C@H]2CC[C@@H](CO)O2)cc1I
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A solution of 2',3'-dideoxycytidine (2.11 g, 10 mmol, Raylo) and mercuric acetate (3.35 g, 10.5 mmol, Fisher) in 50 mL of methanol was refluxed for 19 hours. The resulting white suspension was diluted with methanol (50 mL) and dichloromethane (100 mL). Iodine (3.05 g, 12 mmol) was added and the suspension was stirred at 25°. After 4 hours, the free base form of AG3X4A resin (20 mL, 38 meq, Bio-Rad) was added and hydrogen sulfide was bubbled into the reaction for 15 minutes. Complete precipitation of mercury(II) was verified by TLC. The reaction was filtered through filter aid and the filter aid was washed with 1:1 methanol-dichloromethane. The filtrate was evaporated onto silica gel (10 g) and the loaded silica gel was placed on top of a 150 g silica gel column. Elution with 5%, 10% and 20% methanol in dichloromethane afforded 2.79 g (83%) of iodide 19 as a colorless crystalline solid. Two recrystallizations from boiling water afforded, after vacuum-drying at 50°, large, analytically-pure prisms (mp: d 178°).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=CC=1)([O-])=O.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:19])=[CH:17][CH:16]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
5.55 G. of p-chlorobenzoic acid p-nitrophenyl ester are added to a solution of 2.6 g. of N-(2-aminoethyl)-morpholine in 100 ml. of tetrahydrofuran and the mixture is allowed to stand overnight at room temperature. It is then evaporated to dryness and the residue is taken up in 200 ml. of methylene chloride. The methylene chloride solution is washed three times with 50 ml. of a 1% sodium hydroxide solution each time and twice with 50 ml. of water each time until neutral, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from isopropanol, and 3.1 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:9](Cl)=[O:10])=[CH:6][S:7][CH:8]=1)[CH3:2].C(Cl)Cl.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[C:20]([CH:22]=1)[NH2:21]>C(N(CC)CC)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[C:20]([CH:22]=1)[NH:21][C:9]([C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:8][S:7][CH:6]=1)=[O:10]
Reactant: Nc1cc(Cl)ccc1O
Reactant: CCOc1cscc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cscc1C(=O)Nc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 8.8 g. portion of 4-ethoxy-3-thiophenecarbonyl chloride is dissolved in 100 ml. of methylene chloride and added dropwise to a mixture of 6.6 g. of 5-chloro-2-hydroxyaniline in 100 ml. of methylene chloride and 6.5 ml. of triethylamine. This mixture is stirred at ambient temperature overnight, concentrated to 100 ml. and filtered. The filtrate is allowed to stand overnight and the precipitate which forms is collected, washed with water and dried in vacuo. This combined precipitate is recrystallized from 200 ml. of ethanol, treated with charcoal, filtered through diatomaceous earth and concentrated giving 5'-chloro-4-ethoxy-2'-hydroxy-3-thiophenecarboxanilide as red brown crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.[CH3:11][Si](C[Mg]Cl)(C)C.C(OCC)C>C1COCC1>[CH2:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][CH:9]=[CH2:11]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: O=CCCc1cccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCc1cccnc1
Reaction time: 0.25 h

Procedure:
3-(Pyridin-3-yl)propanal (10 g, 74 mmol) is dissolved in THF (200 ml), and thereto is added a solution of trimethylsilylmethyl magnesium chloride in diethyl ether (100 ml, 100 mmol) under ice-cooling, and the mixture is stirred for 15 minutes. The reaction is quenched with a saturated brine (10 ml), and the mixture is extracted with ethyl acetate (300 ml×2), washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added THF (50 ml) and conc. sulfuric acid (5 ml), and the mixture is heated under reflux for 20 minutes. After being allowed to cool, the reaction solution is neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (200 ml×2). The organic layer is washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-(3-butenyl)pyridine (6.5 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][C@:2]([OH:9])([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].N1C=CN=C1.Cl.[CH3:16][NH:17][O:18][CH3:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:19][O:18][N:17]([CH3:16])[C:3](=[O:4])[C@@:2]([CH3:1])([OH:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CNOC
Reactant: CC(C)[C@](C)(O)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CON(C)C(=O)[C@@](C)(O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a magnetically stirred solution of (8) (59 g, 0.44 mol) in methylene chloride (880 mL) in a 3-L, two-neck, round-bottom flask at 0° C. under a nitrogen atmosphere was added 1,1-carbonyldiimidazole (87 g, 0.54 mol, 1.2 equivalents) in portions. The yellow solution was gradually warmed to room temperature and stirred under a nitrogen atmosphere overnight. To the reaction was added imidazole (60 g, 0.88 mol, 2 equivalents), 4-dimethylaminopyridine (1.6 g, 0.01 mol, 0.03 equivalents), and N,O-dimethylhydroxylamine hydrochloride (53 g, 0.54 mol, 1.2 equivalents). The solution was stirred overnight and then the resulting mixture was washed with 2N aqueous hydrochloric acid (2×600 mL), water (1×800 mL), and saturated aqueous sodium chloride solution (1×800 mL), dried over anhydrous magnesium sulfate, and filtered. The solvent was removed in vacuo to provide 73 g (94% yield) of (9) as a yellow oil. The 1H NMR spectrum of the product was consistent with the material previously prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
The compound of example 392 (100 mg, 0.295 mmol) was dissolved in 3 mL THF and to this reaction mixture, 2-chlorophenyl isocyanate (49.83 mg, 0.324 mmol) was added and stirred at room temperature for 8-10 h. The reaction mixture was concentrated and purified by column chromatography (silica gel, 30-40% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1)=[O:5])#[N:2].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.O>CN(C=O)C>[C:1](/[C:3](=[CH:23]\[C:19]1[O:18][CH:22]=[CH:21][CH:20]=1)/[C:4]([NH:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)Nc1nnc(-c2ccccc2)s1
Reactant: O=Cc1ccco1
Solvent: CN(C)C=O
Solvent: O
Product: N#C/C(=C\c1ccco1)C(=O)Nc1nnc(-c2ccccc2)s1
Temperature: 150 °C

Procedure:
312 mg of 2-cyano-N-(5-phenyl-1,3,4-thiadiazol-2-yl)acetamide and 150 uL of furan-2-carbaldehyde were mixed in 2.5 mL of DMF and heated in a microwave at 150° C. for 15 min. 5 ml of H2O was added and the resulting precipitate was collected and washed with water (4×) to give the crude product. Recrystallization from ethanol gave 180 mg of pure product as a brown solid. MS (M+H, 323); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 6.82 (m, 1H)), 7.43 (d, 1H), 7.49 (m, 4H), 7.87 (m, 2H), 8.15 (s, 1H), 8.22 (br, s, 1H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])[N:6]([CH3:17])[C:5]=1[CH2:18][OH:19].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH2:20]([O:3][C:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH:11]([OH:16])[C:12]([F:15])([F:13])[F:14])[N:6]([CH3:17])[C:5]=1[CH2:18][OH:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(C(O)C(F)(F)F)cc(=O)c(O)c1CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(O)C(F)(F)F)cc(=O)c(OCc2ccccc2)c1CO
Temperature: 25 °C
Yield: 76 %

Procedure:
A 6.00 N sodium hydroxide solution (785 μL, 4.71 mmol) was added to a suspension of 3-hydroxy-2-hydroxymethyl-1-methyl-6-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (1.08 g, 4.26 mmol) in methanol (5 mL). Benzyl bromide (650 μL, 5.46 mmol) was added to the clear solution, and the resulting solution was heated to reflux for 45 min Some solid had separated out in the solution. Analysis of the reaction mixture using HPLC Method 1 (Example 24) indicated that the starting material was consumed. The reaction mixture was allowed to cool down to room temperature, and the first crop of solid product was collected by suction filtration, and washed with acetonitrile. The title compound was thus obtained as a solid product (1.11 g, 76% yield, HPLC Method 1 (Example 24), RT=12.6 min, HPLC purity (peak percent area): 99% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 7.36 (m, 5H), 6.59 (s, 1H), 5.53 (q, J=6.5 Hz, 1H), 5.01 (s, 2H), 4.58 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CCN(C(C)C)C(C)C.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=2[F:35])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.060 g, 0.162 mmol) in dry THF (5 mL) was added DIPEA (3 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0° C. and 2-flurobenzoyl chloride (0.038 g, 0.243 mmol) was added and stirred for 3 h at room temperature. The reaction mass was quenched in water, extracted with DCM:MeOH and concentrated to afford crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.030 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 4.50-4.52 (d, J=8 Hz, 2H), 7.25-7.33 (m, 2H), 7.52-7.55 (m, 2H), 7.63-7.65 (m, 2H), 7.72-7.86 (d, J=2.4 Hz, 1H), 7.83-7.86 (d, J=11.6 Hz, 2H), 8.17-8.20 (d, J=11.6 Hz, 2H), 8.95-8.99 (t, 1H), 12.69 (br s, 1H); MS (m/z): 491.17 (M+H+).
Reaction SMILES: [C:1]1([C:7](=[CH2:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][O:19][C:15]=2[CH:14]=1>C(O)(C)C>[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([CH3:11])[C:8]([OH:10])=[O:9])[CH2:24][CH2:25]3)=[N:18][O:19][C:15]=2[CH:14]=1
Reactant: C=C(C(=O)O)c1ccccc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC(C)O
Product: CC(C(=O)O)(c1ccccc1)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
2-phenylacrylic acid (1.8 g, 12 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.4 g, 11 mmol) in 100 ml dry isopropanol was refluxed for 3 h. The mixture was concentrated in vacuo and taken up in water whereupon NaHCO3 was added until pH 8-9. The formed crystals were isolated, washed with ethyl acetate and dried to give 2.0 g 3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino-2-phenylpropanoic acid. M.p. 194°-200° C.
Reaction SMILES: CO[C:3]1[C:6](=[O:7])[C:5](=[O:8])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:13]=[CH:14][C:15]=1[CH3:16].[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]([CH2:26][NH:25][C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:18]([NH:17][C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[C:10]([NH:9][C:4]3[C:5](=[O:8])[C:6](=[O:7])[C:3]=3[NH:41][CH2:40][CH2:39][O:38][CH3:37])[CH:11]=2)=[O:19])=[CH:28][CH:29]=1
Reactant: COCCN
Reactant: COc1c(Nc2cc(NC(=O)c3sccc3NCc3ccnc4ccccc34)ccc2C)c(=O)c1=O
Product: COCCNc1c(Nc2cc(NC(=O)c3sccc3NCc3ccnc4ccccc34)ccc2C)c(=O)c1=O

Procedure:
EXAMPLE 46 was prepared according to the procedure described in EXAMPLE 3 using N-{3-[(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino]-4-chlorophenyl}-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide (EXAMPLE 44) and 2-methoxyethylamine instead of dimethylamine. MS (ES+): m/z 541.9 [M+1]
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10]O)/[CH3:8])[CH3:3].[CH:12](=[O:16])/[CH:13]=[CH:14]/[CH3:15].C(OC(C)(C)C)(=O)C>>[CH3:8][C:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[CH:9][CH2:10][CH2:15][CH:14]=[CH:13][CH:12]=[O:16]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: C/C=C/C=O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)=CCCC(C)=CCCC=CC=O
Yield: 78 %

Procedure:
110 parts of geraniol, 50 parts of crotonaldehyde and 3.2 parts of t-butyl acetate are heated for six hours at 30 atmospheres pressure and at 150° C in an agitated autoclave having a capacity of 250 parts by volume. Working up gives 85 parts of 7.11-dimethyldodeca-2,6,10-trien-1-al having a boiling point of 93° to 96° C at 0.2 mm. The yield is 78% of theory at a conversion of 74% (based on crotonaldehyde).