Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.O[C:27]1[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:27]3[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: OC1CCN(c2ccncc2)CC1
Reactant: COC(=O)COc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
Diethylazodicarboxylate (0.47 ml) was added dropwise over 30 minutes to a stirred mixture of 1-(4-pyridyl)-4-piperidinol (534 mg), methyl 4-hydroxyphenoxyacetate (546 mg), triphenylphosphine (787 mg) and dry THF (30 ml) in an atmosphere of argon and cooled to 4° C. After 1 hour at 4° C., the mixture was allowed to reach ambient temperature and stirred for 48 hours. The solvent was removed by evaporation and the residue purified by flash chromatography on silica eluting with 5% v/v methanol/dichloromethane. Recrystallisation from ethyl acetate/hexane gave the title compound, 532 mg, as a white solid: m.p. 74°-76° C.; NMR (d6DMSO) δ 8.15(2H, bd), 6.89(6H, m), 4.71(2H, s), 4.50(1H, m), 3.70(2H, m), 3.69(3H, s), 3.23(2H, m), 1.96(2H, m), 1.62(2H, m); m/e 343 (M+H)+ ; calculated for C19H22N2O4 : C, 66.7; H, 6.5; N, 8.2. found: C, 66.2; H, 6.7; N, 8.2%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:36]([N:38]1[CH:42]=[CH:41][C:40]([CH:43]=O)=[N:39]1)[CH3:37]>>[CH2:36]([N:38]1[CH:42]=[CH:41][C:40]([CH2:43][NH:1][C:2]2[CH:3]=[CH:4][N:5]([CH3:27])[C:6]3[C:7]=2[CH:8]=[CH:9][C:10]2[N:19]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=3[C:11]=24)=[N:39]1)[CH3:37]
Reactant: CCn1ccc(C=O)n1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1ccc(CNC2=c3ccc4c5c([nH]c(=O)c-5c3N(C)C=C2)=CCN4c2ccc(F)cc2)n1
Yield: 41.2 %

Procedure:
A stock solution of Example 23e (0.164 M in N,N-dimethylacetamide, 255 mL, 0.042 mmol), acetic acid (4 M in methanol, 200 mL, 0.84 mmol), sodium cyanoborohydride (0.31 M in methanol, 200 mL, 0.063 mmol) and 1-ethyl-1H-pyrazole-3-carbaldehyde (0.40 M in N,N-dimethylacetamide, 156 mL, 0.063 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 50° C., and passed through the reactor at 180 μL, min−1 (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0081 g (41%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 7.57 (m, 2H), 7.07 (d, J=2.75 Hz, 1H), 6.95 (m, 2H), 6.74 (m, 2H), 6.60 (dd, J=8.54, 2.75 Hz, 1H), 6.46 (m, 2H), 6.22 (d, J=2.14 Hz, 1H), 4.28 (s, 2H), 4.10 (q, J=7.12 Hz, 2H), 4.04 (s, 3H), 2.88 (d, J=53.41 Hz, 2H), 1.38 (m, 3H). MS (APCI+) m/z 469.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:24]1([CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH2:26][CH2:25]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCC1CC1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC3CC3)CC1)O2

Procedure:
Compound 122 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (bromomethyl)cyclopropane and conditions outlined in procedure V. M.p.=161-164° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 2.95 (m, 4H), 2.5 (t, 2H), 2.35 (d, 2H), 2.15 (d, 2H), 1.9 (t, 2H), 0.9 (s, 1H), 0.55 (d, 2H), 0.15 (s, 2H); LCMS: 356 [M+H].
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[CH2:19]([C:22]1([CH:29]=[O:30])[CH2:27][CH:26]2[CH2:28][CH:23]1[CH:24]=[CH:25]2)[CH:20]=[CH2:21]>CCCCCC.C1COCC1>[CH2:19]([C:22]1([CH:29]([OH:30])[CH:10]([C:9]2[CH:16]=[CH:17][CH:18]=[C:7]([Cl:6])[CH:8]=2)[N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:27][CH:26]2[CH2:28][CH:23]1[CH:24]=[CH:25]2)[CH:20]=[CH2:21]
Reactant: Clc1cccc(Cn2ccnc2)c1
Reactant: C=CCC1(C=O)CC2C=CC1C2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC1(C(O)C(c2cccc(Cl)c2)n2ccnc2)CC2C=CC1C2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
13.8 ml (20 mmol) of a 1.45 molar solution of n-butyllithium in hexane were added dropwise to a solution of 3.85 g (20 mmol) of 1-(3-chlorobenzyl)-imidazole in 40 ml of absolute THF at -70° C. After stirring for 30 minutes at -70° C., a solution of 4.39 g of 74% purity (20 mmol) 2-allyl-5-norbornen-2-aldehyde in 30 ml of absolute THF was added dropwise at about -70° C. over about 12 minutes. The further procedure was subsequently carried out as described in Example 2. The residue (9.0 g) remaining from the organic component after removing the solvent by distillation was dissolved in diisopropyl ether/hexane 2:1, whereupon crystalline product precipitated. After isolation using 20 ml of acetonitrile, this was boiled briefly, filtered off under suction after cooling the mixture, and washed with acetonitrile. 2.70 g (≅38% yield) of pure 1-(2-allyl-5-norbornen-2-yl)-2-(3-chlorophenyl)-2-(1-imidazolyl)-ethanol were obtained in the form of a mixture, comprising 2 diastereomers, of melting point 134°-135° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31]Cl)[N:18]=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39]([O-])(=[O:42])[CH2:40][OH:41].[Na+].[Na]>C(O)CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][O:41][CH2:40][CH2:39][OH:42])[N:18]=[C:17]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(Cl)c(Oc2c(CCl)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: O=C([O-])CO
Agent: [Na+]
Agent: [Na]
Solvent: OCCO
Product: COc1ccc(Cl)c(Oc2c(COCCO)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
1 g of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide was added to a sodium glycolate solution from 2.5 g of ethylene glycol and 0.12 g of sodium. The reaction mixture was stirred at 80° C. under argon for 72 hours. Thereafter, the ethylene glycol was distilled off and the residue was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic phase was washed with water, dried over sodium sulphate and the solvent was distilled off. The residue was chromatographed over silica gel with ether. There was obtained 0.85g of 4-tert-butyl-N-[5-(2-chloro-5methoxy-phenoxy)-6-(2-hydroxy-ethoxymethyl)-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide. m.p 162°-164° C., MS: M=606.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]2[C@:10]3([CH3:21])[C@@H:15]([CH2:16][CH2:17][C:6]=2[CH:5]=1)[C@@:14]([CH2:19][NH2:20])([CH3:18])[CH2:13][CH2:12][CH2:11]3)[CH3:3]>CCOCC>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]2[C@:10]3([CH3:21])[C@@H:15]([CH2:16][CH2:17][C:6]=2[CH:5]=1)[C@:14]([CH2:19][NH2:20])([CH3:18])[CH2:13][CH2:12][CH2:11]3)[CH3:1]
Reactant: CC(C)c1ccc2c(c1)CC[C@H]1[C@](C)(CN)CCC[C@]21C
Solvent: CCOCC
Product: CC(C)c1ccc2c(c1)CC[C@H]1[C@@](C)(CN)CCC[C@]21C

Procedure:
dl-5-Benzyloxymethyl-cyclopent-2-enyl-4-hydroxy-1-acetic acid (88.5 g.) in ether (1500 ml.) was slowly treated with dehydroabietylamine (92.4 g.) in ether (500 ml.). The precipitated salt (140 g., [α]DMeOH = + 19°) was collected by filtration and was crystallised from benzene (20 ml./g.) to afford a salt (54 g.), [α]D = + 13° (methanol). Two subsequent crystallisations from benzene (50 ml./g; 2 hours at room temperature) gave the dehydroabiethylamine salt of l-5α-benzyloxymethyl-4β-hydroxycyclopent-2-enyl-1β-acetic acid (42 g.), [α]DMeOH = + 10°. A suspension of this salt in ether-water (2:1) was treated with 1.2 equivalents of 5% potassium hydroxide and extracted with ether. The aqueous layer was then treated with 8N sulphuric acid to pH 1.5, saturated with ammonium sulphate and extracted with chloroform to yield the pure l-5α -benzyloxymethyl-4β-hydroxy-cyclopent-2-enyl-1β-acetic acid, which showed [α]D = -26.5°; [α]365° = -78° (CHCl3) and [α]D = -5.4°. [α]365° = -13° (MeOH). The mother liquors from the first benzene crystallisation were diluted with ether to obtain a benzene-ether ratio of 5:4 and stored for 3 hours at 5°. The precipitated salt (48 g., [α]DMeOH = + 27°) was collected by filtration and recrystallised from benzene-ether (1 g. salt, benzene 20 ml., ether 40 ml.) to yield 44 g. of the dehydroabietylamine salt of d-5β-benzyloxymethyl-4α-hydroxy-cyclopent-2-enyl-1α-acetic acid, [α]DMeOH = + 28.8°. In a similar way, the 5α-p-methoxybenzyloxymethyl-4β-hydroxy-cyclopent-2-enyl-1β-acetic acid was obtained from the dl-acid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1)=[O:4].Cl.[F:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C(OC(C)C)(C)C>>[C:12]([C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:28][CH:27]=3)[CH2:22][CH2:23]2)[CH:11]=[CH:10][CH:9]=1)#[N:13]
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: N#Cc1cccc(NC(=O)CCl)c1
Agent: Cl
Solvent: CC(C)OC(C)C
Product: N#Cc1cccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)c1

Procedure:
The title compound is prepared from 2-chloro-N-(3-cyano-phenyl)-acetamide (Example 166a) and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 101-103° C. (diisopropylether)
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C@@H:11]2[NH:16][CH2:15][CH2:14][N:13]([C:17]3[C:26]4[CH:25]=[C:24]([CH3:27])[S:23][C:22]=4[NH:21][C:20]4[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=4[N:18]=3)[CH2:12]2)=[CH:5][CH:4]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C@@H:11]2[N:16]([CH3:36])[CH2:15][CH2:14][N:13]([C:17]3[C:26]4[CH:25]=[C:24]([CH3:27])[S:23][C:22]=4[NH:21][C:20]4[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=4[N:18]=3)[CH2:12]2)=[CH:5][CH:4]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(C(F)(F)F)cc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
Combine 10-((S)-3-[2-(4-trifluromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (325.3 mg, 0.69 mmol), formaldehyde (61.7 μL, 0.76 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (219.8 mg, 1.04 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 298.1 mg (89%) of the title compound as a tan foam: mp 72°, dec; mass spectrum (ion spray): m/z=485.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.O=[C:9]([CH2:14][C:15](OC)=[O:16])[C:10]([O:12][CH3:13])=[O:11]>C(O)(=O)C>[OH:16][C:15]1[N:3]2[N:4]=[C:5]([CH3:7])[N:6]=[C:2]2[N:1]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: COC(=O)CC(=O)C(=O)OC
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)n2nc(C)nc2n1
Yield: 30.7 %

Procedure:
3-Amino-5-methyl-1H-s-triazole (112 mg) and 320 mg of dimethyl 2-oxo-succinate are dissolved in 5 ml of glacial acetic acid. After boiling under reflux for 22 hours the solvent is distilled off in a vacuum. The residue is suspended in warm methanol. After cooling the product is filtered off and washed several times with methanol. After drying in a high vacuum there are obtained 73 mg of methyl 7-hydroxy-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate as a beige powder, m.p.>220° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:7]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([O-:5])=[O:4].[CH2:25](I)[CH3:26].O>CN(C=O)C>[CH2:25]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][C:21]([S:23][CH3:24])=[CH:22][C:6]=1[N+:3]([O-:5])=[O:4])[CH3:26]
Reactant: CSc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc(SC)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a suspension of sodium hydride (65%, 0.21 g (5.76 mmol)) in 4.0 ml of DMF, 2′-nitro-4′-methylthio-p-toluenesulfonanilide (1.50 g (4.43 mmol)) was added with stirring at room temperature. To the resulting mixture, after 30 minutes' stirring at room temperature, ethyl iodide (0.52 ml (6.21 mmol)) was added dropwise and the mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, dilute hydrochloric acid, and saturated aqueous solution of sodium chloride successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was then subjected to silica gel column chromatography with chloroform as eluent to give 1.04 g (64%) of the title compound as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3([CH3:25])[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[CH2:9][CH2:8]2)[C@H:5]2[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:4]2[NH:3]1.Cl>O1CCOCC1>[CH3:25][C:13]1([N:10]2[CH2:11][CH2:12][CH:7]([N:6]3[C@H:5]4[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:4]4[NH:3][C:2]3=[O:1])[CH2:8][CH2:9]2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Tert-butyl 3-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]-3-methyl-pyrrolidine-1-carboxylate (1.85 g, 4.55 mmol) in dioxane was added with 4N HCl solution in dioxane (11.4 mL, 45.5 mmol) and was stirred at room temperature under nitrogen atmosphere overnight. Then solvent was removed under reduced pressure to give the title compound as a white solid (1.3 g), which was used for the subsequent step without further purification. MS (M+1): 307.28.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12]>>[CH3:12][CH:11]([CH3:13])[CH2:10][NH:14][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)CN
Reactant: N#Cc1ccccc1F
Product: CC(C)CNc1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and isobutylamine.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24](OC)=[O:25])=[CH:6][CH:5]=2.[CH2:28]([NH2:34])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1.C([O-])(O)=O.[Na+].[ClH:40]>>[ClH:40].[OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24]([NH:34][CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][O:33]1)=[O:25])=[CH:6][CH:5]=2
Reactant: NCC1CCCO1
Reactant: COC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC1CCCO1)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Yield: 27 %

Procedure:
Starting materials: methyl 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxylate and tetrahydrofurfurylamine, but heated at reflux for 2 h. The cooled mixture was poured into a saturated NaHCO3 solution and concentrated in vacuo. The residue was suspended in methanol/dichloromethane, (1:1), silica gel (˜2 g) was added and the mixture was re-concentrated in vacuo. The resulting residue was purified on a silica gel column using dichloromethane/methanol, (100:1 to 25:2 and 1% ammonia solution in water (25%)), as the eluent to give the base. Yield: 27%: 1H NMR (DMSO-d6, 300 MHz) δ 14.75 (br s, 1H), 11.37 (br s, 1H), 10.69 (s, 1H), 8.50 (t, J=5.51 Hz, 1H), 8.22 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 4.25 (s, 2H), 4.02-3.60 (m, 6H), 3.44-3.22 (m, 4H), 3.20-3.03 (m, 2H), 1.95-1.78 (m, 4H), 1.70-1.55 (m, 1H); MS (ES) m/z 437 (M++1). The base was transferred to the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:6]([CH:15]=[CH2:16])[N:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1nc(Cl)nc(N2CCCCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1nc(N)nc(N2CCCCC2)n1
Temperature: 100 °C

Procedure:
To a solution of 221 (358 mg, 1.68 mmol) in dry toluene (7 mL) was added tributyl(vinyl)tin (514 μL, 1.76 mmol) followed by Pd(PPh3)4 (97 mg, 0.084 mmol) and the reaction mixture was heated at 100° C. for 16 h in a sealed tube. Then, the reaction mixture was allowed to cool to room temperature, concentrated, and purified directly by flash chromatography on silica gel (AcOEt/hexane: 10/90→30/70) to afford the title compound 222 (containing tributyltin chloride).
Reaction SMILES: C(O)(=O)C.[O:5]1[C:6](=[C:10]1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)C([O-])=O.[K+].C1(C)C=CC=CC=1>O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:6]=[O:5])=[CH:12][CH:13]=1
Reactant: COc1ccc(C2=C(C(=O)[O-])O2)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(CC=O)cc1
Temperature: 25 °C

Procedure:
70 ml of an aqueous solution of 3.64 g of acetic acid are added dropwise to a mixture, heated to the boiling point, of 14 g (59 mmol) of potassium (E)-α,β-epoxy-p--methoxycinnamate, 112 ml of toluene and 28 ml of water. After 5 minutes the mixture is cooled to room temperature. The organic phase is washed with water and then with aqueous potassium carbonate solution. The aqueous washings are extracted with toluene. The organic phase is dried azeotropically. The yield of p-methoxyphenylacetaldehyde in the solution obtained amounts to 92-94%.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=1[O:17][CH3:18])#[N:4].[CH3:19]I.Cl>C1COCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=1[O:17][CH3:18])#[N:4]
Reactant: CI
Reactant: CCOC(=O)Cc1ccc(C#N)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension solution of NaH (0.18 g, 4.6 mmol, 60% dispersion in mineral oil) in THF (50 mL) at 0° C. under N2 atm was added a solution of ethyl (4-cyano-3-methoxyphenyl)acetate (1.0 g, 4.6 mmol) in THF (10 mL) drop-wise and the mixture was stirred for 30 min at the same temperature. The mixture was then allowed to warm to ambient temperature. The mixture was then allowed to cool back to 0° C. Methyl iodide (0.28 mL, 4.6 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was acidified with 1 M hydrochloric acid and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc 15/1) to give ethyl 2-(4-cyano-3-methoxyphenyl)propanoate.
Reaction SMILES: [CH3:1][C:2]1O[C:6]2[CH2:8][CH2:9][O:10][CH2:11][C:5]=2[C:4](=[O:12])[CH:3]=1.[NH3:13]>>[CH3:1][C:2]1[NH:13][C:6]2[CH2:8][CH2:9][O:10][CH2:11][C:5]=2[C:4](=[O:12])[CH:3]=1
Reactant: N
Reactant: Cc1cc(=O)c2c(o1)CCOC2
Product: Cc1cc(=O)c2c([nH]1)CCOC2

Procedure:
Compound C1 (1.0 g) and aqueous ammonia solution (density, 0.91 g/ml; 15 ml) were heated at 120° C. in a sealed tube for 10 hours. Volatile material was removed by evaporation and the residue azeotroped with toluene (2×20 ml). The residue was recrystallised from a mixture of methanol and ethyl acetate to give 2-methyl-1,5,7,8-tetrahydropyrano[4,3-b]-pyridin-4-one (B1) (0.70 g), as an off-white solid, m.p. >285° C.; NMR (d6 -DMSO): 2.2(s,3H), 2.45-2.6(m,2H), 3.8(t,2H), 4.3(t,2H), 5.8(s,1H) 11.1(br s, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10]O)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][CH:6]1[I:18])[CH2:2][CH2:3][CH3:4].O=S(Cl)Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30])[CH3:24].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:5]1[C:9]([CH2:10][NH:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][CH:6]1[I:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(CO)=C(c2ccccc2)NC1I
Reactant: CCOc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCN1C(CNCc2cccc(OCC)c2)=C(c2ccccc2)NC1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1-Butyl-2-iodo-4-phenyl-3H-imidazol-5-yl)-methanol (1.96 g), prepared by the method given in Example 2, step 2, is dissolved in 20 mL CH2Cl2. The solution is cooled to 0° C. and 3 equivalents of SOCl2 are added. The resulting solution is stirred at room temperature for 2 hours and then evaporated to dryness. The residue is dissolved in 5 mL of DMF and added to an ice cooled solution of 2 equivalents of 3-ethoxybenzylamine and 2 equivalents K2CO3 in 10 mL DMF. The mixture is stirred overnight at room temperature. The reaction is quenched with 20 mL water, extracted with EtOAc (3×30 mL), washed with water and brine, and dried over Na2SO4. Concentration and purification via silica gel chromatography provides (1-Butyl-2-iodo-4-phenyl-3H-imidazol-5-ylmethyl)-(3-ethoxy-benzyl)-amine.