Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[O:31])[O:29][C:28]([CH3:33])([CH3:32])[O:27][C:26]=2[CH:34]=1.O.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:23]=[CH:24][C:25]4[C:30](=[O:31])[O:29][C:28]([CH3:32])([CH3:33])[O:27][C:26]=4[CH:34]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A solution of 4-[(4-butylphenyl)ethynyl]benzaldehyde (2.0 g, 7.63 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) and 7-amino-2,2-dimethyl-4H-1,3-benzodioxine-4-one (1.47 g, 7.63 mmol) in toluene (30 mL) was heated at reflux for 96 hrs with azeotropic removal of water. The reaction mixture was concentrated off under reduced pressure. MeOH (15 mL) and THF (15 mL) were then added, and the resulting mixture chilled at 0° C. Sodium borohydride (375 mg, 9.9 mmol) was added portionwise and the mixture was stirred for 1 hr at 0° C., then 3 hrs at room temperature. The reaction mixture was diluted with EtOAc (60 mL) and washed with an aqueous solution of NaOH (3×15 mL, 1N). The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. Et2O (100 mL) was added and the resulting white precipitate was filtered off to give 2.2 g (66%) of the title compound as a white solid. HPLC, Rt: 5.62 min (purity: 93.6%). LC/MS, M−(ESI): 438.3, M+(ESI): 440.2. 1H NMR (CDCl3) δ: 7.71 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 6.32 (m, 1H), 6.01 (m, 1H), 4.38 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 1.60 (s, 6H), 1.65-1.50 (m, 2H), 1.42-1.28 (m, 2H), 0.91 (t, J=7.5 Hz, 3H).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (35 mg), potassium carbonate (37 mg), and piperidine (23 mg), and the mixture was stirred at 75° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (35 mg, yield 89%).
Reaction SMILES: C([Al](CC)CC)C.[CH3:8][C:9](=[CH:11][CH2:12][CH2:13][CH:14]([CH2:16][CH:17]=[O:18])[CH3:15])[CH3:10].C(OC(=O)C)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:15][C@H:14]1[CH2:16][C@@H:17]([OH:18])[C@H:11]([C:9]([CH3:10])=[CH2:8])[CH2:12][CH2:13]1
Reactant: CC(C)=CCCC(C)CC=O
Agent: CC[Al](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
8.0 g (13.6 mmol) of the ligand Ia2-3 were dissolved in 140 ml of toluene at room temperature under argon. 4.78 ml (9.09 mmol) of a 25% strength triethylaluminum solution in toluene were added and the mixture was after-stirred for 1 h. The resulting catalyst suspension was cooled to 0° C. and, over the course of 5 h, a mixture of 70.0 g (0.45 mol) of citronellal and 0.7 g (6.86 mmol, 1% by weight with regard to citronellal) of acetic anhydride was added. The mixture was after-stirred for 1 h at 0° C. and for 12 h at room temperature. At the end of the experiment, 100 ml of 8% strength sodium hydroxide solution were added and the phases separated. The organic phase was dried with sodium sulfate and the solvent was removed under reduced pressure. The crude product was distilled at 1 mbar over a short column. At a top temperature of 58° C., 68.4 g of isopulegol with the following composition (in each case GC area %) were obtained: isopulegol: 98.4%, neo-isopulegol: 0.6%, neoiso-isopulegol: 0.4%. This corresponds to a chemical yield of 97%, based on all diastereomers and a diastereoselectivity of 99:1 (isopulegol: other diastereomers).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[N:12]=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[O:14][C:15]=2[S:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19]N=2)=[CH:7][N:6]=1)=O.[CH3:31][Mg]Br>C1COCC1.[NH4+].[Cl-]>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([S:16][C:15]2[O:14][C:13]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[N:12][C:11]=2[C:8]2[CH:7]=[N:6][C:5]([CH3:3])=[CH:10][N:9]=2)=[CH:31][CH:19]=1
Reactant: C[Mg]Br
Reactant: COC(=O)c1cnc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cnc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cc2)cn1
Yield: 31.7 %

Procedure:
A solution of methyl-5-[5-[(4-chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazine-2-carboxylate (Example 1) (24 mg, 0.05 mmol) in THF (5 mL) was treated with methylmagnesium bromide (0.2 mL, 0.5 mmol, 3.0 M in THF) at rt. Upon completion of the reaction as judged by TLC analysis, the solution was diluted with saturated aq NH4Cl solution and extracted with EtOAc. The organic layer was removed, dried over MgSO4, filtered and concentrated giving rise to an oil. The oil was purified on silica gel to afford the title compound (6.3 mg). LC/MS: m/e 397.0 (M+H)+. 1H NMR (500 MHz, Acetone-d6): δ 2.55 (s, 3H), 7.46 (m, 5H), 8.06 (m, 2H), 8.50 (s, 1H), 8.55 (s, 1H), 9.10 (d, J=1.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:11][C:12]([N:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15]2)=[O:13])[CH:4]=1.[OH:22][C:23]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:32][N:31]=2)[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>CO.C(O)(C)C>[N:37]1[CH:38]=[CH:39][CH:40]=[N:41][C:36]=1[C:33]1[CH:34]=[CH:35][C:30]([C:23]2([OH:22])[CH2:28][CH2:27][CH:26]([NH:19][C@H:16]3[CH2:17][CH2:18][N:14]([C:12](=[O:13])[CH2:11][O:10][CH2:9][C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:8]=[CH:7][N:6]=4)[CH2:15]3)[CH2:25][CH2:24]2)=[N:31][CH:32]=1
Reactant: N[C@H]1CCN(C(=O)COCc2cc(C(F)(F)F)ccn2)C1
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)cn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(COCc1cc(C(F)(F)F)ccn1)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncccn4)cn3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S)-1-({[4-(trifluoromethyl)pyridin-2-yl]methoxy}acetyl)pyrrolidin-3-amine (47 mg, 0.15 mmol) and 4-hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexanone (41 mg, 0.15 mmol) in methanol (2 mL) and isopropanol (2 mL) was added sodium triacetoxyborohydride (36 mg, 0.17 mmol). After being stirred at room temperature overnight, EtOAc was added. The solution was washed with NaHCO3 solution and water, dried (MgSO4) and concentrated. Purification by HPLC provided two isomers of the title compound. MS (M+H) 557.2 for both isomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][NH:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCN)c(C)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNCCc1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Reaction time: 1.67 h
Yield: 87.2 %

Procedure:
To a solution of 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)ethanamine (1.0 g, 2.65 mmol) in dioxane (6.6 mL) was added di-tert-butyldicarbonate (730 μL, 3.19 mmol), followed by aqueous sodium hydroxide (2.5 M solution, 1.28 mL, 3.19 mmol). The reaction mixture was stirred for 100 min, At this time, HPLC analysis indicated complete conversion to product. The mixture was then diluted in ethyl acetate (25 mL), transferred to a separatory funnel, and washed with 1 M aqueous sodium bicarbonate (2×10 mL), saturated ammonium chloride (10 mL), and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The carbamate product was then dissolved in THF (13 mL), and the solution was treated with lithium aluminum hydride (800 mg). The resulting slurry was warmed to reflux and stirred for 90 min, after which HPLC analysis indicated consumption of starting material. The mixture was subsequently added slowly to 75 mL 2.5 M aqueous sodium hydroxide stirred over ice. The resulting grey suspension was stirred for 10 min, during which time the solids became white. To the suspension was added 100 mL isopropyl acetate, and the resulting mixture was filtered, and transferred to a separatory funnel. The organics were removed and the aqueous layer washed with 50 mL isopropyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 900 mg of 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-methylethanamine. 1H-NMR (400 MHz, CD3OD) 7.51-7.30 (m, 10H), 4.72 (s, 3H), 2.84 (s, 2H), 2.42 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H) ppm.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[C:3]([C:16]([O:18]C)=[O:17])[CH:2]=1.[OH-].[K+].O.C(O)C>O1CCOCC1>[CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[C:3]([C:16]([OH:18])=[O:17])[CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2

Procedure:
Stir a mixture of 136 mg. (0.5 mmole) of the ester of Example 7, 65.9 mg. (1 mmole) of 85% aqueous potassium hydroxide, 0.65 ml. of water, 3.25 ml. of ethanol, and 0.325 ml. of dioxane under argon at room temperature for 12 hours. Evaporate the mixture to dryness. Dissolve the residue in water and acidify with acetic acid. Recover the precipitate by filtration and wash with water. Dry in vacuo over calcium chloride and recrystallize from acetonitrile to obtain the title product (sinters and darkens at 237° C., m.p. 243° C. dec.).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1)=[O:4].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.[Na]>C(#N)C.C(OCC)(=O)C>[N:16]1([CH:2]([CH3:15])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=2)=[O:4])[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cn1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C(=O)c1ccc(C(F)(F)F)cn1)n1cncn1
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-bromopropionyl)-5-trifluoromethyl-pyridine (5.8 g.) in acetonitrile (65 ml.) was added sodium 1,2,4-triazole (2.0 g.) and the solution was stirred for 90 minutes. The acetonitrile was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure to give a yellow gum. Chromatography on silica, using petroleum ether (bp (60°-80°): ethyl acetate 60/40 v/v as eluent, gave 2-[2-(1,2,4-triazol-1-yl)propionyl]-5-trifluoromethylpyridine as a pale yellow oil. Nmr in deuteriochloroform: δ1.88 (3H, d); 6.62 (1H, q); 7.9 (1H, s); 8.14 (2H, m); 8.36 (1H, s); 8.94 (1H, d).
Reaction SMILES: C([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][C:20](=[O:22])[NH2:21])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[H][H]>CO.O.[C].[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][C:20](=[O:22])[NH2:21])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Into a 200 ml three-necked flask was charged 5.0 g (14.2 mmol) of Z-L-Ala-L-Gln, and the peptide was dissolved in 100 ml of a mixture of methanol and water (methanol:water =7:3) and stirred with a magnetic stirrer. After the air in the flask had been replaced with nitrogen, 0.8 g of 2% by weight of palladium-carbon was added thereto, and the protective group was eliminated in a stream of hydrogen. After 2 hours, the completion of the reaction was confirmed by thin layer chromatography, and then the palladium-carbon was filtered off. The filtrate was concentrated to 20 ml under reduced pressure, and 40 ml of isopropyl alcohol was added thereto. The resulting mixture was stirred for 30 minutes, during which time crystals precipitated. The crystals were collected by filtration, washed with isopropyl alcohol and then dried under reduced pressure to give 2.8 g (12.9 mmol) (90%) of L-Ala-L-Gln.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.O>[Br:1][C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:26]([C@@H:25]([NH2:24])[CH3:29])=[N:9][C:4]=2[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1ccc(F)c(Br)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
A mixture of 3-bromo-4-fluoro-N2-phenylbenzene-1,2-diamine (500 mg, 1.79 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (370 mg, 1.95 mmol), HOAt (266 mg, 1.95 mmol), 4-methylmorpholine (0.43 mL, 3.91 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (376 mg, 1.95 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with DCM (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in dioxane (10 mL) and HCl (12N, 1.5 mL) added. The reaction mixture was stirred at RT for 18 h then made basic by addition of 1N NaOH. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (102 mg, 17%). LCMS (Method C): RT 2.28 min [M+H]+ 334.1/336.1. Chromatography purification afforded also (S)-2-amino-N-(3-bromo-4-fluoro-2-phenylaminophenyl)propionamide (384 mg) which was dissolved in 4N HCl in dioxane (10 mL) and heated at 70° C. for 3 h. The volatiles were removed in vacuo to afford (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride salt (434 mg, 60%). 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (2H, s), 7.83 (1H, dd, J=8.80, 4.57 Hz), 7.71-7.58 (5H, m), 7.38 (1H, dd, J=9.65, 8.80 Hz), 4.17-4.07 (1H, m), 3.56 (2H, s), 1.42 (3H, d, J=6.80 Hz)
Reaction SMILES: C(O[CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]4[S:26][CH:27]=[C:28]([CH:30]([CH3:32])[CH3:31])[N:29]=4)[C:20]([F:33])=[CH:19][N:13]3[C:14](=[O:18])[C:15]=2[CH:16]=O)[CH2:5]1)=O.[C:34]([O:38][C:39]([CH:41]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[O:61]1CCC[CH2:62]1>>[F:33][C:20]1[C:21]([CH2:23][CH2:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]([CH3:32])[CH3:31])[N:29]=2)=[CH:22][C:12]2[N:13]([CH:19]=1)[C:14](=[O:18])[C:15](/[CH:16]=[CH:41]/[C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:40])=[C:10]([N:6]1[CH2:7][CH2:8][CH2:9][CH:4]([CH:62]=[O:61])[CH2:5]1)[N:11]=2
Reactant: CC(C)c1csc(CCc2cc3nc(N4CCCC(OC=O)C4)c(C=O)c(=O)n3cc2F)n1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Product: CC(C)c1csc(CCc2cc3nc(N4CCCC(C=O)C4)c(/C=C/C(=O)OC(C)(C)C)c(=O)n3cc2F)n1
Yield: 84 %

Procedure:
The 1-{7-fluoro-3-formyl-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}-3-piperidyl formate (145 mg, 0.307 mmol) obtained in (K) was dissolved in tetrahydrofuran (5 ml), added with tert-butoxycarbonylmethylene-triphenylphosphorane (1.38 g, 3.68 mmol) and refluxed by heating for 2 days. The reaction mixture was concentrated, and the resulting residue was purified by preparative TLC (chloroform:methanol=100:4) to obtain the title compound (147 mg, 84%) as yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27]>CC#N>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][NH:27][CH2:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:10][CH:11]=1
Reactant: COCCCN
Reactant: CS(=O)(=O)OCCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCNCCCc1ccc(Br)cc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A mixture of the product of step (i) (272 g, 0.93 mol), K2CO3 (256 g, 1.86 mol), methoxypropylamine (199 g, 2.22 mol) in MeCN (1.5 L) was stirred at 80-90° C. under N2 atmosphere for 16 hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to remove MeCN. MTBE (1 L) and H2O (1 L) were charged to the resulting mixture and washed with aqueous 1N—HCl (1 L). The aqueous phase was collected and basified by aqueous 2.5N—NaOH to pH=9-10, to afford the subtitle compound (ii) in solution, which was used for next step directly.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:33].O>C1COCC1>[CH3:33][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)=[O:9]
Reactant: O=C(Nc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-phenyl-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (100 mg, 0.252 mmol, example 9 (step 3) in THF (1 mL) was added sodium hydride (12 mg, 0.505 mmol) slowly. The resulting mixture was stirred at RT for 15 min and iodomethane (16 μL, 0.252 mmol) was added. The mixture was stirred at RT for 16 h. Then, H2O (2 mL) was added and the mixture was extracted with EtOAc (2×2 mL). The combined organic extracted were dried over MgSO4 and concentrated. The residue was then dissolved in DMSO (1 mL) and the solution mixture was purified by preparative HPLC (10%-400% of MeCN (0.1% TFA)/H2O (0.1% TFA) to give the title compound as an off-white solid. MS (ESI, positive ion) m/z: 411 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.[NH2:16][CH:17](C)[CH2:18][CH2:19][OH:20]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc2ccc(Br)cc2nc1Cl
Reactant: CC(N)CCO
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 7-bromochloro-3-nitroquinoline (10.00 g, 34.78 mmol) in dichloromethane (140 mL) was added triethylanine (10.2 mL, 73.1 mmol). The solution was cooled to 0° C., and 3-amino-1-butanol (2.80 mL, 36.5 mmol) was added. The solution was stirred overnight at ambient temperature and then filtered to collect a precipitate. The precipitate was washed with dichloromethane and water. The filtrate was washed with saturated aqueous sodium bicarbonate and then added to the precipitate. The mixture was concentrated under reduced pressure. Methanol and toluene were added several times and removed under reduced pressure. The resulting solid was dried under high vacuum to provide 11.34 g of 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=O)[NH:9]2)=[CH:5][CH:4]=1)#[N:2].[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]3)=[O:14])[NH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2cc(C(=O)O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](NC(=O)c2cc3ccc(C#N)cc3[nH]2)CC1

Procedure:
In the same manner as in Example 1 (2), 6-cyano-2-indolecarboxylic acid (244 mg, 1.31 mmol) and t-butyl trans-(4-aminocyclohexyloxy)acetate (300 mg, 1.31 mmol) were condensed. The reaction mixture was purified by silica gel column chromatography (chloroform/methanol=50/1-1/1) to give 465 mg of t-butyl trans-[4-[(6-cyano-2-indolyl)carbonylamino]cyclohexyloxy]acetate as a brown solid (89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[N:13]([O-])=O.[Na+].[CH2:17]([O:19][C:20](=[O:29])[CH2:21][CH:22](C(=O)C)[C:23](=[O:25])[CH3:24])[CH3:18]>C(O)C.O.C(O)C.N1C=CC=CC=1.O>[CH2:17]([O:19][C:20]([CH2:21][C:22](=[N:13][NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)[C:23](=[O:25])[CH3:24])=[O:29])[CH3:18]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(=NNc1ccc(S(N)(=O)=O)cc1)C(C)=O
Reaction time: 0.25 h

Procedure:
To a suspension of 10 g. (58.1 mmoles) of 4-aminobenzenesulfonamide in 50 ml of 1:1 ethanol/water was added 7.3 ml. of concentrated hydrochloric acid. To the cooled mixture was added in portions 4.41. g (63.9 mmoles) of sodium nitrite in 5 ml. of water. The mixture was allowed to come to room temperature and after 15 minutes was poured into a solution of 11.9 g. (63.9 mmoles) of ethyl-3-acetyl-4-oxopentanoate in 12.2 ml. of pyridine, in 25 ml. of ethanol. An orange solid began to separate which was collected after 30 minutes by filtration. After drying, 24.3 g. of material was obtained.