Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C(CC2C=CN=C(N3CCN([C:20]([O:22]CC4C=CC=CC=4)=[O:21])CC3)C=2)=NC([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=3)[N:31]=2)=N1>CC(O)=O.Br>[CH:20]([OH:22])=[O:21].[F:45][C:42]([F:43])([F:44])[O:41][C:38]1[CH:37]=[CH:36][C:35]([C:32]2[N:31]=[CH:30][O:34][N:33]=2)=[CH:40][CH:39]=1
Reactant: Cn1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nc1Cc1ccnc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Agent: Br
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc(-c2ncon2)cc1
Product: O=CO
Temperature: 40 °C
Reaction time: 1 h
Yield: 144.8 %

Procedure:
To a solution of benzyl 4-(4-((2-methyl-5-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-2H-1,2,4-triazol-3-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate (200 mg, 0.30 mmol) in AcOH (1 mL), HBr (2 mL, 48% in H2O) was added at RT. The mixture was stirred at 40° C. for 1 h, and then concentrated to give the crude product, which was purified by pre-HPLC (Mobile phase: A=0.01% HCOOH/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge (C18, 5 um, 30 mm*150 mm) to afford compound 5-(1-methyl-5-(2-(piperazin-1-yl)pyridin-4-yl)methyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole formate salt as a white solid (120 mg, 61%). MS (ES+) C22H21F3N8O2 requires: 486, found: 487[M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.32 (bs, 1H), 8.22 (d, J=8.5 Hz, 2H), 8.08 (d, J=5.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 2H), 6.81 (s, 1H), 6.58 (d, J=5.5 Hz, 1H), 4.27 (s, 2H), 4.00 (s, 3H), 3.6-3.48 (m, 4H), 2.99-2.85 (m, 4H).
Reaction SMILES: C([C:9]1[C:10]([C:15]([OH:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)C1C=CC=CC=1.NC1C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Product: O=C(O)c1ccccn1
Temperature: 0 °C

Procedure:
1 mole of the benzoyl-pyridine-carboxylic acid (II) or the (heterocyclic-carbonyl)-pyridine-carboxylic acid (IV) and about 0.9 to 1.5 moles, preferably 1.0 to 1.2 moles of the heterocyclic compound (III) or the aniline compound (V) are added to about 3 to 30 moles of concentrated sulfuric acid, acetic anhydride or polyphosphoric acid, and the resulting mixture is allowed to react at a temperature of about 30° to 130° C for a period of from about 2 to 10 hours. The reaction product is then poured into 1 to 5 liters of ice-water to hydrolyze or dilute the condensing agent, and the resulting aqueous solution was made weakly acidic or neutral with dilute aqueous sodium hydroxide. Benzene or toluene is added thereto followed by stirring to transfer any unreacted heterocyclic compound or aniline compound to the benzene or toluene layer, which is then removed by separation. The residual aqueous layer is adjusted to a pH of about 11 to 12 with dilute aqueous sodium hydroxide and the precipitated solid is filtered, washed successively with water and a small amount of ethanol and dried to obtain in good yield a lactone color former of the pyridine-carboxylic acid represented by the formula (I) as substantially colorless of slightly colored crystals. Alternatively, the residual aqueous layer as obtained above, after removal of the benzene or toluene layer, is adjusted to a pH of 11 to 12 with dilute aqueous sodium hydroxide, and benzene or toluene is added to the resulting aqueous solution followed by stirring to transfer the lactone color former of pyridine-carboxylic acid to the benzene or toluene layer, which was then recovered by separation. Benzene or toluene was distilled off from the benzene or toluene layer. The residue was washed successively with water, a small amount of ethanol, benzene, lizroin or petroleum ether and dried. Further alternatively, the above reaction product is poured into 1 to 5 liters of ice-water to hydrohyze or dilute the condensing agent, and the resulting aqueous solution was adjusted to a pH of 11 to 12 with dilute aqueous sodium hydroxide. Benzene or toluene is added thereto followed by stirring to transfer the lactone color former of pyridine-carboxylic acid into the benzene or toluene layer which is then recovered by separation. The benzene or toluene layer is worked up in the same manner as described above. Thus, a substantially colorless or slightly colored lactone color former of pyridine-carboxylic acid represented by the formula [I] can be obtained in high yield. If necessary, the lactone color former of pyridine-carboxylic acid thus obtained can be recrystallized. The present invention, will now be illustrated by reference to the following Examples, but they are not to be construed as limiting the present invention.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[C:16]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:3][C:2]([F:1])([F:14])[F:15])[C:5](=[O:13])[CH2:6]2)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: O=C1Cc2ccccc2N1CC(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CC(=O)N2CC(F)(F)F

Procedure:
To a solution of 1-(2,2,2-trifluoro-ethyl)-1,3-dihydro-indol-2-one (2.0 g, 9.3 mmol) and acetyl chloride (0.86 mL, 12 mmol) in carbon disulfide (40 mL) was added aluminum trichloride (7.4 g, 56 mmol) by portions. The mixture was heated to reflux for 3 hours, then cooled. The liquid phase was decanted and the residue was quenched carefully with ice, then water. The solids were filtered, washed with water, dried and recrystallized from acetone/hexanes to give a pale pink solid, mp 170-171° C. Yield 1.23 g (51%).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=O)[CH2:14]1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26](=[NH:28])[NH2:27])[CH3:22]>C(O)C>[CH2:21]([O:23][C:24]([C:25]1[CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][N:2]=2)[C:14]2[C:13](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]=2[NH:27][C:26]=1[NH2:28])=[O:29])[CH3:22]
Reactant: O=Cc1nccc2ccccc12
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1nccc2ccccc12

Procedure:
Upon heating a solution of 6.3 g of isoquinolin-1-aldehye, 4.5 g of cyclohexane-1,3-dione and 5.2 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-4-(isoquinol-1-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 272°C (ethanol) is obtained.
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: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
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 saline, 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: S(Cl)(Cl)=O.[OH:5][C:6]1[C:11](=[O:12])[C:10]([CH:13](O)[C:14]([F:17])([F:16])[F:15])=[CH:9][NH:8][C:7]=1[CH3:19].CO.[Cl:22]CCl>C(#N)C>[Cl:22][CH:13]([C:10]1[C:11](=[O:12])[C:6]([OH:5])=[C:7]([CH3:19])[NH:8][CH:9]=1)[C:14]([F:17])([F:16])[F:15]
Reactant: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1O
Reactant: ClCCl
Solvent: CC#N
Solvent: CO
Solvent: O=S(Cl)Cl
Product: Cc1[nH]cc(C(Cl)C(F)(F)F)c(=O)c1O
Reaction time: 0.5 h

Procedure:
Thionyl chloride (2.5 mL, 33.7 mmol) was added to a suspension of 3-hydroxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (1.50 g, 6.7 mmol) in acetonitrile (33 mL) at room temperature. The resulting mixture was stirred for 30 min as a clear solution resulted. The progress of the reaction was monitored by TLC (methanol:dichloromethane, 1:10, v:v), which indicated consumption of the starting material. The reaction mixture was evaporated to dryness to give crude 5-(1-chloro-2,2,2-trifluoro-ethyl)-3-hydroxy-2-methyl-1H-pyridin-4-one as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][S:15]([CH3:17])=[O:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.[CH2:46]([NH2:54])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>ClCCl>[CH3:17][S:15]([CH2:14][CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:54][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:12])=[O:16]
Reactant: CCCCCCCCN
Reactant: CS(=O)CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)C(CCS(C)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
To a mixture of 2-((tert-butoxycarbonyl)amino)-4-(methylsulfinyl)butanoic acid (10.0 g, 37.7 mmol) and HOBt (6.35 g, 41.5 mmol) in dichloromethane (200 mL) at 0° C. was added triethylamine (10.5 mL, 75.4 mmol) and EDAC (7.95 g, 41.5 mmol). After stirring for 20 minutes octylamine was added and the solution was allowed to warm to room temperature and stirred for 3 days. The reaction was washed with saturated sodium bicarbonate (2×100 mL), 1N HCl (2×100 mL), and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oil which solidified upon standing. The solid was purified by silica gel chromatography with 0-5% methanol/dichloromethane to give a white solid (13.1 g, 92%). m/z 377 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[C:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=N[CH:25]=[CH:26][CH:27]=4)[C:18]3=[O:28])[CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[C:29]1(C)C=CC=CC=1>C(N(CC)CC)C.Cl[Pd]Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[C:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:29][CH:23]=4)[C:18]3=[O:28])[CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C1CC(=C2CCN(c3cccnc3)C2=O)c2ccc(Cl)cc2N1
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(=C2CCN(c3ccccc3)C2=O)c2ccc(Cl)cc2N1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of intermediate 4b (370 g) in toluene (5.2 lit), Triethylamine (248 ml), Triphenilphosphine (7.4 g) and PdCl2 (2.52 g) were added. The resulting solution was warmed to 100° C. and stirred for 2 h. The suspension was chilled to 20-25° C. and toluene (2.6 ml) was added. The reaction mixture was washed with NH4Cl 8% (3×5.2 lit) and water (5.2 lit). The organic layer was filtered over a celite pad and it was washed with toluene (1 lit); then it was distilled under vacuum (T=50° C.; P=60 mbar) to reach 6.3 lit. After cooling to T=20-25° C., isooctane (5.2 lit) was dropped over 30 min. The precipitate was stirred for 2 h 30 min then it was filtered and washed with a mixture toluene/isooctane 1/1 (1.85 lit). The yellow solid was dried in vacuum at T=40° C. for 18 h to obtain the title compound as a yellow solid 210 g.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1cc(Cl)ccc1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,5-Dichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,5-dichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:8][CH2:9][CH2:10][NH2:11].C1C=CC=CC=1.[Cl:18][CH:19]([Cl:23])[C:20](Cl)=[O:21]>O>[Cl:18][CH:19]([Cl:23])[C:20]([N:11]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[S:8][CH2:9][CH2:10]1)=[O:21]
Reactant: O=C1CCCCC1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NCCS
Solvent: c1ccccc1
Solvent: O
Product: O=C(C(Cl)Cl)N1CCSC12CCCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
From a boiling mixture of 9.8 g. (0.1 moles) of cyclohexanone and 7.7 g. (0.1 moles) of 2-mercaptoethylamine in 100 ml. of benzene the water formed is continuously distilled off. Boiling is continued until 1.8 ml. of water are separated. The reaction mixture is then cooled and 11 g. of a 40% aqueous sodium hydroxide solution are added followed by dropwise addition of 14.7 g. (0.1 moles) of dichloroacetyl chloride, with external salt/ice cooling. Mixture is stirred for a further two hours at room temperature and washed with aqueous hydrochloric acid solution and subsequently with water. From the neutral mixture obtained benzene is distilled off in vacuo to give 17.2 g. (0.064 moles) of a white powder. Recrystallization from absolute ethanol yields a white crystalline product melting at 149° to 151° C. The structure of the named compound can be verified by IR spectrum analysis.
Reaction SMILES: [OH:1][C@@H:2]1[C@:10]2([CH3:11])[C@H:5]([CH2:6][C@@H:7]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)=[CH:37][CH:36]=3)[C@@H:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=3)[CH2:9]2)[CH2:4][CH2:3]1.[C:48](OC(=O)C)(=[O:50])[CH3:49].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:48]([O:1][C@@H:2]1[C@:10]2([CH3:11])[C@H:5]([CH2:6][C@@H:7]([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)=[CH:39][CH:40]=3)[C@@H:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[CH:14][CH:13]=3)[CH2:9]2)[CH2:4][CH2:3]1)(=[O:50])[CH3:49]
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCSCCCC(F)(F)C(F)(F)F)cc3)[C@H](c3ccc(OC4CCCCO4)cc3)C[C@@H]1CC[C@@H]2O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@H]2C[C@@H](c3ccc(OC4CCCCO4)cc3)[C@@H](c3ccc(OCCCCCSCCCC(F)(F)C(F)(F)F)cc3)C[C@@]21C
Yield: 86 %

Procedure:
The solution of 1.43 g (2.51 mmol) of the compound that is presented in Example 2c is reacted analogously to Example 1, and after working-up, a mixture that consists of the title compound is isolated, and (1S,3S,4R,6S,9S)-9-hydroxy-4-[4-(tetrahydropyran-2-yloxy)phenyl]-1-methyl-3-[4-(10,10,11,11,11-pentafluoro-6-thia-undecyloxy)phenyl]-bicyclo[4.3.0]nonane, which is dissolved in 25 ml of anhydrous pyridine, is mixed with 3 ml of acetic anhydride and a spatula tip full of 4-dimethylaminopyridine, and it is stirred for 2 hours at 23° C. It is poured into saturated sodium bicarbonate solution, extracted several times with dichloromethane, the combined organic extracts are washed with saturated sodium chloride solution and dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on about 400 ml of fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 1.57 g (2.16 mmol, 86%) of the title compound is isolated as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22]C(=O)C)[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.C(#N)C.[OH-].[NH4+]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNC(=O)CC3)c(F)c2)C(=O)O1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC#N
Product: NC[C@H]1CN(c2ccc(N3CCNC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 47.5 °C
Reaction time: 18 h

Procedure:
An ice cold, stirred mixture of the product of Example 2, Step 1 (0.22 g, 0.50 mmol) in tetrahydrofuran (THF; 15 mL), under nitrogen, is treated dropwise during 2 minutes, with a lM solution of tetrabutylammonium fluoride in THF (1.5 mL). The mixture is kept in the ice bath for 10 minutes and at ambient temperature (24° C.) for 1 hour 25 minutes, diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with mixtures of 25 methanol-methylene chloride containing 3-6% methanol gave 0.15 g of the alcohol, a compound of formula 9 (Scheme 1) where R is hydrogen: MS(ES) m/z 324 (M+H+). A stirred suspension of the alcohol (0.15 g, 0.46 mmol) in methylene chloride (15 mL) and THF (8 mL), under nitrogen, is treated with triethylamine (0.5 mL, 1.4 mmol) and then portionwise during 1 minute at ambient temperature, with 0.14 g (0.56 mmol) of m-nitrobenzenesulfonyl chloride. The mixture is stirred for 90 minutes, mixed with additional methylene chloride (10 mL) to give a solution and kept at ambient temperature for 1 hour. It is then kept for several days at -11° C., diluted with methylene chloride, washed with saturated sodium bicarbonate, water and brine, dried (Na2SO4) and concentrated to give 0.21 g of the m-nitrobenzenesulfonate, a compound of formula 10 (Scheme 1). A stirred mixture of the m-nitrobenzenesulfonate (0.21 g, 0.44 mmol), acetonitrile (10 mL), 2-propanol (10 mL) and 29% ammonium hydroxide (10 mL) is warmed at 45-50° C. under a Dry Ice-acetone condenser for 4.5 hours and kept at ambient temperature for 18 hours. Additional ammonium hydroxide (5 mL) is added and the mixture is warmed at 45-50° C. for 4.5 hours, kept at ambient temperature for 1 hour, treated with 5 mL of ammonium hydroxide and kept at ambient temperature for 18 hours. It is then concentrated to give a yellow solid which is chromatographed on silica gel with mixtures of methanol-methylene chloride containing 5-7.5% methanol followed by 8% methanol-0.2% ammonium hydroxide-methylene chloride to give the titled product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23].C(O)C>C(O)(=O)C>[CH3:26][C:20]1[NH:19][C:10]([CH3:11])=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CC(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C)=C(c2ccccc2)C1c1ccc(F)cc1
Yield: 111.1 %

Procedure:
24.0 g (0.1 mol) of 1-(4-fluorophenyl)-2-phenylbuten-3-one, 23 g (0.2 mol) of methyl 3-amino-crotonate and 6 ml (0.1 mol) of glacial acetic acid are heated under reflux overnight in 150 m of ethanol, heated under reflux for 18 h after addition of 11.5 g (0.1 mol) of methyl 3-aminocrotonate and 3 ml of glacial acetic acid and heated under reflux for 18 h once more after repeated addition of 11.5 g (0.1 mol) of methyl 3-aminocrotonate and 3 ml of glacial acetic acid. The solvent is removed in vacuo, 80 ml of methanol are added to the residue, undissolved material is filtered off with suction, the methanolic solution is concentrated in vacuo and excess aminocrotonate is distilled off from the residue at 73° C.-90° C./18 mbar and subsequently at 60° C.-70° C. 0.2 mbar. 37.5 g of crude product are obtained as a brittle fused mass.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=O)[NH:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.[OH-].[NH4+:35]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]2[NH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:35]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NCC(=O)c1ccccc1
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C

Procedure:
The product prepared in Step A above (3.55 g, 9 mmol), NH4OAc (ammonium acetate) (20.8 g, 270 mmol) and AcOH (acetic acid) (30 mL) were combined at room temperature and the reaction mixture was warmed on a steam bath for about 3 hours. The reaction mixture was then cooled to room temperature and poured into an ice slurry mix (400 g). To this mixture was added concentrated ammonium hydroxide (50 mL) and ethyl ether. The layers were separated, and the aqueous phase washed with a second portion of ethyl ether. The organic phases were combined, dried over MgSO4 filtered, and concentrated under reduced pressure to yield a brown foam. This sample was purified by preparative HPLC to yield the purified title compound as a white powder. LC indicated the sample was 96% pure at 214 nm.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[NH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[OH:24])[CH2:17]1.[BH4-].[Na+]>CO.ClCCl>[OH:24][CH:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:22][N:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([CH2:15][NH:14][CH2:12][C:9]2[CH:10]=[CH:11][C:5]3[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)[CH2:17]1
Reactant: COc1ccc2nccc(C(O)CN3CCC[C@@H](CN)C3)c2c1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2nccc(C(O)CN3CCC[C@@H](CNCc4ccc5c(c4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Molecular sieve, type 3A, (1.082 g) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.095 g, 0.54 mmol) were added to a solution of (3S)-2-(3-aminomethyl-piperidin-1-yl)-1-(6-methoxy-quinolin-4-yl)-ethanol (0.171 g, 0.54 mmol) in MeOH (1.6 ml) and dichloromethane (3.8 ml). The reaction mixture was stirred at room temperature for 16 hours and sodium borohydride (0.054 g, 1.43 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 9/1 1% NH4OH).