Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[C:31]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)([CH3:34])([CH3:33])[CH3:32].CN(C=O)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:41][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:36]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1coc(Oc2cccc(C(C)(C)C)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 182.4 %

Procedure:
In a 5 ml glass tube were placed 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.10 mmol), K2CO3(17 mg, 0.12 mmol), 3-tert-butyl phenol (18 mg, 0.12 mmol), DMF (1 mL), and a magnetic stir bar. The vial was sealed with septum and placed into the Microwave cavity. The vial was irradiated in a Microwave synthesizer at 130° C. for 10 min. The reaction mixture was diluted with EtOAc, and washed with saturated ammonium chloride and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (90 mg, 80%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[O:14][C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:17](=[O:19])[CH:18]=2)=[CH:7][CH:6]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[O:14][C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][C:17](=[O:19])[CH:18]=2)=[CH:7][CH:6]=1
Reactant: O=c1cc(C=Cc2ccc([N+](=O)[O-])cc2)oc(-c2ccccc2)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C=Cc2cc(=O)cc(-c3ccccc3)o2)cc1

Procedure:
A solution of concentrated hydrochloric acid (0.2 ml) in ethanol (20 ml) was added to a stirred refluxing suspension of 2-[2-(4-nitrophenyl)-ethenyl]-6-phenyl-4H-pyran-4-one (8.5 g) and iron powder (4.5 g) in ethanol (80 ml) and water (20 ml). The stirred mixture was heated under reflux for 5 hours, adding further concentrated hydrochloric acid (0.2 ml) after 2 hours. The hot mixture was filtered and the filtrate was evaporated under vacuum. The solid residue was crystallised from chloroform-petroleum ether 60°-80° C. to give 2-[2-(4-aminophenyl)ethenyl]-6-phenyl-4H-pyran-4-one (mp 192°-194° C.).
Reaction SMILES: C[N:2]1[C:6]([CH:7]2[CH2:12][CH:11](C(OCC)=O)[CH2:10][CH2:9][N:8]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[N:5][N:4]=[N:3]1.N1(C(N2C=CN=C2)=O)C=CN=[CH:29]1.[CH2:40]([O:42][C:43](=[O:48])[CH2:44][C:45]([O-])=[O:46])[CH3:41].[K+].[Cl-].[Mg+2].[Cl-]>C1COCC1>[CH2:40]([O:42][C:43](=[O:48])[CH2:44][C:45]([CH:11]1[CH2:10][CH2:9][N:8]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH:7]([C:6]2[N:2]=[N:3][N:4]([CH3:29])[N:5]=2)[CH2:12]1)=[O:46])[CH3:41]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnnn2C)C1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn(C)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
1-(Benzyloxycarbonyl)-2-(2-methyl-2H-tetrazol-5-yl)piperidine-4-carboxylic acid (0.828 g, 2.40 mmol) (reference compound 36) was dissolved in THF (7 mL) and then di(1H-imidazol-1-yl)methanone (0.583 g, 3.60 mmol) was added. The reaction was stirred overnight at room temperature (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (0.816 g, 4.80 mmol) and anhydrous magnesium chloride (0.457 g, 4.80 mmol) were suspended in THF (7.00 mL) and stirred at 50° C. under nitrogen overnight and then allowed to cool to room temperature (flask 2). The content of flask 1 was added to flask 2 and stirred under nitrogen over the weekend (72 h). The reaction was quenched by addition of 2 M HCl. The mixture was extracted three times with EtOAc, the combined organic phase was evaporated and purified on a 50 g Biotage column with heptane/EtOAc 88/12-100/0 over 12 CV. Benzyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-2H-tetrazol-5-yl)piperidine-1-carboxylate (499 mg, 59%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.22-1.31 (m, 3H), 1.72-1.83 (m, 1H), 2.00-2.08 (m, 1H), 2.41 (dt, 1H), 2.70-2.78 (m, 1H), 2.88-2.95 (m, 1H), 3.35-3.63 (m, 3H), 3.99-4.07 (m, 1H), 4.12-4.20 (m, 2H), 4.28 (s, 3H), 5.11-5.21 (m, 2H), 5.59 (t, 1H), 7.27-7.40 (m, 5H). MS m/z 416 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:21](N1CCOCC1)=[O:22]>O1CCCC1>[O:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:21]=[O:22])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(COc2ccccc2)cc1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(COc2ccccc2)cc1
Temperature: 78 °C
Reaction time: 0.67 h
Yield: 100.6 %

Procedure:
To a tetrahydrofuran solution (50 mL) of 1-bromo-4-phenoxymethyl-benzene (4.69 g, 17.8 mmol) described in Manufacturing Example 86-1-1 was added dropwise n-butyl lithium (16.8 mL, 1.59 M hexane solution, 26.7 mmol) at −78° C. After 40 minutes of stirring at 78° C., N-formylmorpholine (2.25 g, 19.6 mmol) was added to this mixture, which was then stirred for a further 30 minutes at that temperature. This mixture was partitioned into diethyl ether and water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.8 g). This compound was used in the subsequent reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.[CH3:15][I:16]>O1CCCC1>[I-:16].[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[N+:10]1[CH:14]=[CH:13][N:12]([CH3:15])[CH:11]=1
Reactant: N#Cc1ccc(-n2ccnc2)c(Br)c1
Reactant: CI
Solvent: C1CCOC1
Product: Cn1cc[n+](-c2ccc(C#N)cc2Br)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(2-Bromo-4-cyanophenyl)imidazole (5.4 g, 22 mmol, 1 eq) and methyl iodide (15.4 g, 109.0 mmol, 5 eq) are dissolved in tetrahydrofuran (50 ml) and stirred at room temperature for 16 hours. The precipitate formed is filtered off and washed with ethanol.
Reaction SMILES: C([O:8][C:9](=[O:31])[CH2:10][NH:11][C:12]([C:14]1[C:15](=[O:30])[N:16]([CH3:29])[C:17]2[C:22]([C:23]=1[OH:24])=[CH:21][CH:20]=[C:19]([C:25]([O:27]C)=[O:26])[CH:18]=2)=[O:13])C1C=CC=CC=1.O.[OH-].[Li+]>O1CCOCC1.O>[C:9]([CH2:10][NH:11][C:12]([C:14]1[C:15](=[O:30])[N:16]([CH3:29])[C:17]2[C:22]([C:23]=1[OH:24])=[CH:21][CH:20]=[C:19]([C:25]([OH:27])=[O:26])[CH:18]=2)=[O:13])([OH:31])=[O:8]
Reactant: COC(=O)c1ccc2c(O)c(C(=O)NCC(=O)OCc3ccccc3)c(=O)n(C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ccc(C(=O)O)cc21

Procedure:
Methyl 3-((2-(benzyloxy)-2-oxoethyl)carbamoyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylate (26 mg, 61 μmol) (65689-17-3) was dissolved in 12 ml dioxane/H2O (5:1) and to this was added lithium hydroxide monohydrate (613 μl, 613 μmol) as a 1M aqueous solution. The resultant mixture was heated to 60 C for 4 hrs. The solvent was removed in vacuo and the aqueous layer was acidified with 2N HCl to pH2. Following dilution with EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc (3×). The organic layer was washed with H2O and brine, then dried over Na2SO4. The solvent was removed by rotovap, azeotroping with benzene (3×) to give a light yellow solid which was rinsed with DCM followed by MeOH.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2occc2c1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4occc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using benzofuran-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.20 (dd, J=2.0, 1.0 Hz, 1H), 7.66 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.91 (dt, J=8.6, 1.0, 0.8 Hz, 1H), 8.14-8.24 (m, 2H), 8.47 (dt, J=7.9, 2.0 Hz, 1H), 8.60 (d, J=1.4 Hz, 1H), 8.82 (dd, J=4.7, 1.7 Hz, 1H), 9.28 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:30][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Reactant: O=C1CCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCCCC2)cc1
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 19.8 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred for 1 hour at -70° with 3.05 g of cycloheptanone, and heated to 25°. Then the mixture is combined with water, extracted twice with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.9 g of crude 4-[1-hydroxycyclohept-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:14][C:15]([CH3:17])=[O:16]>CCO.O.[OH-].[Na+]>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:11]/[C:4](=[O:3])/[CH:5]=[CH:6]/[C:7]2[CH:10]=[CH:17][C:15]([O:16][C:2]([F:1])([F:12])[F:13])=[CH:14][CH:8]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccc(OC(F)(F)F)cc1)/C=C/c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
A colorless solution of 4-(trifluoromethoxy)-benzaldehyde (0.75 mL, 5.3 mmol) in acetone (0.19 mL, 2.6 mmol), EtOH (5 mL) and H2O (1 mL) was treated with aq. 10% NaOH solution (˜12 drops). The reaction mixture was stirred for 2 h at room temperature and the colorless solution turned into a yellow suspension. The precipitate was filtered, washed with H2O and dried in vacuo to obtain NW254 as a pale yellow solid (275 mg, 25%). mp: 112-115° C. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.74 (d, 3J=16.1 Hz, 2H, Hvin), 7.67 (d, 3J=8.5 Hz, 4H, HAr), 7.28 (d, 3J=8.2 Hz, 4H, HAr), 7.06 (d, 3J=15.9 Hz, 2H, Hvin.). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.2 (C), 150.6 (C), 141.8 (CH), 133.3 (C), 129.8 (CH), 126.0 (CH), 121.2 (CH). MS (EI) m/z: 402.1 (M+). Anal. calcd for C19H12F6O3: C, 56.73; H, 3.01. Found: C, 56.44; H, 3.10%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[C:39]5[CH:38]=[C:37]6[C:40]([CH3:48])([CH3:47])[C:41]7[C:46]([C:36]6=[CH:35][C:34]=5[C:33]5[C:28]4=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:45][CH:44]=[CH:43][CH:42]=7)=[CH:23][CH:22]=3)=[CH:17][CH:16]=1)[C:10]1[CH:9]=[C:8]3[C:49]([CH3:57])([CH3:56])[C:50]4[C:55]([C:7]3=[CH:6][C:5]2=1)=[CH:54][CH:53]=[CH:52][CH:51]=4.[B:58]1(B2OC(C)(C)C(C)(C)O2)[O:62][C:61]([CH3:64])([CH3:63])[C:60]([CH3:66])([CH3:65])[O:59]1.C([O-])(=O)C.[K+].ClCCl>O1CCOCC1>[CH3:65][C:60]1([CH3:66])[C:61]([CH3:64])([CH3:63])[O:62][B:58]([C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[C:39]6[CH:38]=[C:37]7[C:40]([CH3:48])([CH3:47])[C:41]8[C:46]([C:36]7=[CH:35][C:34]=6[C:33]6[C:28]5=[CH:29][CH:30]=[CH:31][CH:32]=6)=[CH:45][CH:44]=[CH:43][CH:42]=8)=[CH:23][CH:22]=4)=[CH:17][CH:16]=2)[C:10]2[CH:9]=[C:8]4[C:49]([CH3:57])([CH3:56])[C:50]5[C:55]([C:7]4=[CH:6][C:5]3=2)=[CH:54][CH:53]=[CH:52][CH:51]=5)[O:59]1
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccc(Br)cc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccc(B8OC(C)(C)C(C)(C)O8)cc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21

Procedure:
7.1 g (9.0 mmol) of 4-(7-bromo-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-10-yl)-4′-(12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-10-yl)biphenyl, 2.5 g (9.85 mmol) of bis(pinacolato)diborane and 2.6 g (26 mmol) of potassium acetate are suspended in 500 ml of dioxane. 0.22 g (0.27 mmol) of 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride complex with dichloromethane is added to this suspension. The reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, washed three times with 150 ml of water and subsequently evaporated to dryness. The residue is recrystallised from toluene. The yield is 6.8 g (8 mmol, 90%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.[Br:9][CH:10]([CH:13]=O)[CH:11]=O>C(O)(=O)C>[Br:9][C:10]1[CH:11]=[N:1][C:2]2[N:6]([N:5]=[C:4]([CH2:7][OH:8])[N:3]=2)[CH:13]=1
Reactant: Nc1nc(CO)n[nH]1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Product: OCc1nc2ncc(Br)cn2n1
Temperature: 60 °C

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (6.29 g, 33.12 mmol) in acetic acid (25 ml) was added bromomalonaldehyde (5 g, 33.12 mmol). The mixture was heated at 60° C. for hours, and then cooled to room temperature. The light yellow solid was formed. After the solid were removed by filtration followed by drying in vacuum oven provides the light yellow solid as desired product, the filtrate was concentrate by rotary evaporation to give yellow oil. The crude oil was purified by flash chromatography (2% MeOH in CH2Cl2) to give the desired product as light yellow solid (combine total 6.5 g, 86% yield). 1H NMR (300 MHz, DMSO-D6) δ ppm 4.65 (d, J=5.46 Hz, 2 H) 5.50–5.67 (m, 1 H) 8.94 (d, J=2.45 Hz, 1 H) 9.83 (d, J=2.26 Hz, 1 H). MS: (APCI) 230 (M+H)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[CH:21]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22]1.[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:35](Cl)=[O:36]>>[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34]([C:35]([N:8]2[CH2:13][CH2:12][C@H:11]([N:27]3[CH2:28][CH2:29][N:24]([CH:21]4[CH2:23][CH2:22]4)[CH2:25][CH2:26]3)[C@H:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9]2)=[O:36])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(C3CC3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=526.1 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-phenyl-piperidin-4-one, N-cyclopropyl-piperazine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:39])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][C:29]3[N:34]=[CH:33][C:32]4[O:35][CH2:36][CH2:37][O:38][C:31]=4[CH:30]=3)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:45]1[O:46][CH:47]=[CH:48][N:49]=1)CCC>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:38]1[C:31]2[CH:30]=[C:29]([CH2:28][N:20]([CH:17]3[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]4[C:10]5[C:5](=[N:4][CH:3]=[C:2]([C:45]6[O:46][CH:47]=[CH:48][N:49]=6)[CH:11]=5)[CH:6]=[CH:7][C:8]4=[O:39])[CH2:15][CH2:16]3)[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[N:34]=[CH:33][C:32]=2[O:35][CH2:36][CH2:37]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(Br)cc32)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(-c4ncco4)cc32)CC1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of 0.10 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate in 2 mL of dioxane, 90 mg of 2-tributylstannyloxazole and 17 mg of bis(tri-tert-butylphosphine)palladium(0) were added under a nitrogen atmosphere, and the mixture was heated under reflux while stirring for 6 hours 30 minutes. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=98:2 to 95:5 to obtain 87 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(1,3-oxazol-2-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[N:14]=2)[N:9]=[CH:8][C:7]=1[F:18])[CH3:2].Br[CH2:21][C:22]#[N:23].O>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[N:14]=2)[N:9]=[CH:8][C:7]=1[F:18])[CH2:21][C:22]#[N:23])[CH3:2]
Reactant: CCOC(=O)Cc1c(F)cnc2ccc(OC)nc12
Reactant: N#CCBr
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)c1c(F)cnc2ccc(OC)nc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
LiRMDS in THF (1M; 12.5 mL) was added at −78° C. during 15 min to a solution of (3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-acetic acid ethyl ester (3.00 g; prepared in analogy to the corresponding methyl ester described in WO 2007/122258) in THF (30 mL). The resulting orange mixture was stirred at −78° C. for 2 h. Bromoacetonitrile (1.13 mL) was added dropwise and the reaction mixture was further stirred at −78° C. for 2 h. The reaction mixture was treated with water and extracted with EA. The combined org. phases were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by CC (Hept/EA 2:1 to 1:1) affording a yellow oil (3.09 g; 89.7% yield).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[NH2:10][C@H:11]([C:19]([NH2:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[OH:20][C:19]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[N:21]=1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1CCCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1nc2c(nc1Cc1ccccc1)CCCC2
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A methanol (30 ml) solution of 1,2-cyclohexanedione (13.44 g, 0.12M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1M) dissolved in methanol (200 ml) under cooling below -30° C., and aqueous 12.5N NaOH (20 ml) was added dropwise thereto. The reaction mixture was stirred under -30° C. for 30 mins., whereafter cooling was removed and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (15 g) was added after 10 mins. stirring, the methanol then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was washed with water, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product (19.7 g, yield: 82.1%).
Reaction SMILES: [C:1]([CH:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH:4]=O)#[N:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=O)=O.[C:31]([O:34][CH2:35][CH2:36]S)(=[O:33])C.[O-]CC.[Na+]>ClCCl.C(Cl)(Cl)Cl>[NH2:2][C:1]1[C:3]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[CH:4][S:27][C:26]=1[C:31]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CC(=O)OCCS
Reactant: CC(C)(C)OC(=O)N1CCC(C(C#N)C=O)CC1
Reactant: CS(=O)(=O)Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1scc(C2CCN(C(=O)OC(C)(C)C)CC2)c1N
Yield: 22 %

Procedure:
The tert-butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate (926 mg, 3.68 mmol) obtained in Step 4 of Example 1 was dissolved in dichloromethane (8 mL), a solution of triethylamine (0.66 mL, 4.78 mmol) and methanesulfonyl chloride (0.31 mL, 4.05 mmol) in dichloromethane (2 mL) was added dropwise under ice-cooling, followed by stirring under ice-cooling for 1 hour. The reaction liquid was diluted with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue (1.58 g) was dissolved in dichloromethane (20 mL), 1,8-diazabicyclo[4,3,0]-7-undecene (2.13 mL, 17.2 mmol) and 2-mercaptoethyl acetate (0.31 mL, 4.05 mmol) were added under ice-cooling, followed by stirring under ice-cooling for 3 hours. The reaction liquid was diluted with chloroform, and washed with a 1 N aqueous hydrochloric acid solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue (3.26 g) was dissolved in ethanol (20 mL), and then sodium ethoxide (2.0 g, 29.4 mmol) was added, followed by heating under reflux for 3 hours. The reaction liquid was concentrated under a reduced pressure, and the obtained residue was dissolved in chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=50:1→30:1) to give tert-butyl 4-[4-amino-5-(ethoxycarbonyl)thiophen-3-yl]piperidine-1-carboxylate (287 mg, 22.0%) as a pale yellow amorphous.