Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:25]>>[NH2:25]/[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[C:6]1\[C:2](=[O:1])[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[S:5]\1
Reactant: N
Reactant: O=C(c1ccccn1)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccn1
Yield: 27 %

Procedure:
Prepared as in Example 1 from (3-hydroxybenzo-[b]thien-2-yl)-2-pyridinyl-methanone, phosphorus(V) chloride and concentrated ammonia with a yield of 27% of theory. M.p. 128°-130° C. (ethyl acetate) C14H10N2OS (254.30): Calc.: C-66.12%; H-3.96%; N-11.02%; S-12.61%; Found: C-66.34%; H-4.09%; N-11.45%; S-12.70%.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([O:44]CC)=[O:43].NN>O1CCCC1.C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([OH:44])=[O:43]
Reactant: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: NCCCCCCc1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(F)cc12
Temperature: 50 °C

Procedure:
A mixture of (E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (The synthesis of this compound was described in EXAMPLE 160B as an intermediate.) (270 mg) and hydrazine (0.030 ml) in tetrahydrofuran (1.00 ml) and ethanol (3 ml) was heated at 50° C. overnight and concentrated. The residue was dissolved in tetrahydrofuran and methanol and then aqueous 10% NaOH was added. The resulting was heated at 50° C. overnight and concentrated. The residue was purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.17 (dd, J=8.44, 1.07 Hz, 1H), 7.84-7.89 (m, 1H), 7.60 (dd, J=9.21, 4.30 Hz, 1H), 7.41-7.56 (m, 4H), 7.32-7.40 (m, 1H), 7.01-7.11 (m, 1H), 6.84 (d, J=7.06 Hz, 1H), 4.80 (t, J=7.21 Hz, 2H), 4.12 (t, J=5.83 Hz, 2H), 2.94-3.06 (m, 2H), 2.75 (t, J=8.29 Hz, 2H), 2.20-2.35 (m, 2H), 1.43-1.63 (m, 4H), 1.27-1.36 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-:18])(=[S:17])[CH3:16].[K+].[Na+].[I-]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:17][C:15](=[O:18])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: CC([O-])=S
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 173821.91 %

Procedure:
To a solution of 6.9 g (0.02 mol) of 4-bromo-piperidine-1-carboxylic acid tert-butyl ester in DMF (18 mL) are added 5.25 g (0.012 mmol) potassium thioacetate, followed by a catalytic amount of NaI (0.35 g, 10 mol %) at room temperature. After complete addition, the reaction is heated to 50° C. for 20 h. The reaction mixture is partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer is dried over Na2SO4, filtered and the solvent is removed under reduced pressure to afford 5.41 g of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester as a brown oil. Yield: 81%; ES-MS: m/z 245 [M+H—CH3], 160 [M+H—C5H9O2]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.37-1.64 (11H, m), 1.78-1.99 (2H, m), 2.25-2.35 (3H, m), 3.06 (2H, ddd, J=13.63, 10.43, 3.05 Hz), 3.61 (1H, tt, J=10.28, 4.04 Hz), 3.76-3.96 (2H, m)
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:24])[CH:22]=[CH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCC(C(=O)OC(C)(C)C)CC1
Reaction time: 5 h

Procedure:
Next, 20.3 g of piperidine-4-carboxylic acid t-butyl ester is dissolved in 100 ml of CH2Cl2 and cooled in an ice bath. Under a nitrogen atmosphere, 12 ml of triethylamine and then, 8.2 ml of acryloyl chloride solution in CH2Cl2 are added dropwise to the ester solution. This mixture is completely mixed by stirring for 5 hrs. Thereafter, this mixture is washed three times with 20 ml of 1 N HCl, washed another three times with 20 ml of NaHCO3 and then washed once with 25 ml of brine water, and dried over MgSO4 to obtain N-acryloyl-piperidine-4-carboxylic acid t-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.Br[C:25]1N2C(C(N)=NC=N2)=CC=1>>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=3)[N:6]2[N:5]=[C:4]([CH3:25])[N:3]=1
Reactant: Nc1ncnn2c(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CC1
Product: Cc1nc(N)c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)n2n1

Procedure:
The title compound was prepared in the same manner described for the preparation of tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate and substituting 7-bromo-2-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine for 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine. 1H-NMR (CD3OD): δ 7.02 (s, 1 H), 6.83 (d, 1 H), 6.62 (d, 1 H), 4.13 (s, 2 H), 3.64 (s, 2 H), 2.62 (d, 2 H), 2.33 (s, 3 H), 1.49 (s, 9 H). MS: LC/MS (+esi), m/z=330 [M+H]. RT=2.47 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[CH3:23]I>CN(C=O)C>[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[N:15]([CH3:23])[C:16](=[O:21])[C:17]([F:19])([F:18])[F:20]
Reactant: CI
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(C)C(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred suspension of NaH (112 mg, 2.80 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0° C. was added 3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester (750 mg, 2.55 mmol) portion wise. The resulting mixture was stirred for 1 h, then MeI (175 mL, 2.80 mmol) was added and the progress of the reaction was followed by LCMS. Upon consumption of 3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester, the reaction mixture was quenched with aqueous NH4Cl, and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane to provide 2-[methyl-(2,2,2-trifluoro-acetyl)-amino]-3-nitro-benzoic acid methyl ester. MS m/z: 275.0 (M+H)+.
Reaction SMILES: N#N.[CH:3](/[C:11]1[O:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>C(Cl)Cl.O>[Si:22]([O:17][CH2:16][C:14]1[N:15]=[C:11](/[CH:3]=[CH:4]/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:12][CH:13]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: OCc1coc(/C=C/c2ccccc2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N#N
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (E)-(2-styryloxazol-4-yl)methanol (5.40 g, 26.8 mmol) in CH2Cl2 (56.0 mL) was treated at rt with tert-butylchlorodimethylsilane (8.52 g, 53.67 mmol) followed by imidazole (3.69 g, 53.67 mmol) and the resulting suspension was stirred for 1 h at rt. Water was added. The aq. layer was extracted with and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (gradient from hept to 9:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (9:1 hept-EA)=0.35. LC-MS-conditions 07: tR=1.08 min, [M+H]+=316.13.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:38][C:39]1[NH:40][CH:41]=[C:42]([CH:44]=O)[N:43]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:44][C:42]4[N:43]=[C:39]([CH3:38])[NH:40][CH:41]=4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Cc1nc(C=O)c[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C3CCN(Cc4c[nH]c(C)n4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (250 mg, 0.503 mmol), 2-methyl-1H-4-imidazolecarbaldehyde (83 mg, 0.755 mmol), sodium triacetoxyborohydride (159 mg, 0.755 mmol) and glacial acetic acid (30 mg, 0.554 mmol) were mixed in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol/ammonium hydroxide (95:5:0.5 to 80:20:05) as mobile phase to give N2-[4-(4-amino-1-{1-[(2-methyl-1H-4-imidazolyl)methyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (215 mg, 72%). 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.23 (m, 7H), 3.00 (m, 2H), 3.41 (s, 2H), 3.96 (s, 3H), 4.04 (s, 3H), 4.78 (m, 1H), 6.72 (s, 1H), 7.15 (m, 1H), 7.32 (m, 4H), 7.78 (d, J=8.43 Hz, 1H), 7.70 (d, J=7.92 Hz, 1H), 8.11 (d, J=7.92 Hz, 1H), 8.24 (s, 1H), 9.44 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 0.8 mL/min.): RT=2.00 min. MH+=591.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C1C=CN=CC=1.C(O)C>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[S:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: Sc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Sc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (1.8 g, 5.0 mmol, prepared in analogy to the one in Example 17-1), benzenethiol (0.66 g, 6.0 mmol) and N,N-dimethylpyridin-4-amine (0.74 g, 6 mmol) in dry ethanol (40 mL) was stirred at room temperature for 3 days. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column (gradient eluting with 10-20% ethyl acetate in hexanes) to afford 1.0 g of the desired product (yield was 45%).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][OH:6])[CH2:2]1.Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[H-].[Na+]>CC1CCCO1>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:6][CH2:5][CH:3]2[CH2:4][O:1][CH2:2]2)=[CH:14][CH:13]=1)(=[O:17])=[O:16]
Reactant: OCC1COC1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CBr)cc2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(COCC3COC3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of oxetan-3-ylmethanol (7 mg, 0.075 mmol) and 4-(bromomethyl)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (31 mg, 0.075 mmol) in 2-methyltetrahydrofuran (2-MeTHF) (1 mL) stirred under nitrogen at room temperature was added sodium hydride (60% dispersed in oil, approximately 2 mg, 0.075 mmol). The reaction mixture was stirred at 20° C. for 3 hours then quenched with water (75 uL). The solvent was removed under a stream of nitrogen to give the crude product. The crude was then purified by mass directed autoprep (ammonium carbonate modifier). The appropriate fractions were concentrated under a stream of nitrogen to give the required product, 2.4 mg. LCMS [LCMS1] Rt 1.34 min, m/z (ES+) 418 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[OH:29])=[CH:12][CH:11]=1.Cl[CH2:34][C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=2[CH:50]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:34][C:35]2[CH:36]=[CH:37][C:38]3[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=3[CH:50]=2)=[CH:14][CH:15]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(F)c3)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(F)c4)cc3)cc21

Procedure:
Analogously to Method D, 1.1 g of tert-butyl 4-{4-[3-(3-fluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.687 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as an opaque oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=5.97.
Reaction SMILES: C(C=C)=O.O1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:11]1[CH:16]=[CH:15]C=[CH:13][CH:12]=1>>[CH3:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:13][CH2:12][CH2:11][CH2:16][CH3:15]
Reactant: c1ccccc1
Reactant: C1CCOCC1
Agent: C=CC=O
Product: CC=CCCCCCCC

Procedure:
In this example, inverse electron demand D-A reaction of acrolein with 3,4-tetrahydropyran is described. The procedure involves refluxing of 0.056 g of acrolein, 1.68 g of tetrahydropyran and 0.30 g of the catalyst prepared according to example 1 above in 10 ml of benzene at 60 (C 20 h. The catalyst was filtered off. After evaporation of solvent, the residue was chromatographed over silica gel column by eluting with 5% acetone/petroleum ether to give 0.12 g of endo adduct, 1,9-dioxabicyclo[4.4.05,10 ]dec-2-ene
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17](O)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[N:30]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17](=[O:18])[NH2:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.6 %

Procedure:
To a solution of (S)-3-(4-benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic acid (5.00 g, 13.5 mmol) and 1-hydroxybenzotriazole monohydrate (2.50 g, 16.1 mmol) in N,N-dimethylformamide (50 ml) were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (3.10 g, 16.1 mmol) and 28% aqueous ammonia solution (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:ethyl acetate=2:1-1:1) to give tert-butyl (S)-[2-(4-benzyloxyphenyl)-1-carbamoylethyl]carbamate (1.53 g, yield 31%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.CC[N:12]([CH2:15][CH3:16])[CH2:13]C.N1CCC1>CN(C=O)C>[N:12]1([C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:9])[CH2:13][CH2:16][CH2:15]1
Reactant: CCN(CC)CC
Reactant: Cn1cc(C(=O)O)cn1
Agent: C1CNC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)N2CCC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol; CAS Nr. 5952-92-1) was combined with DMF (10.0 ml) to give a colorless solution. Et3N (2.41 g, 3.32 ml, 23.8 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, 2.8 g, 8.72 mmol) were added and the reaction mixture was stirred at RT for 1 h. Azetidine (475 mg, 8.33 mmol) was added and the stirring was continued overnight. DMF was partially removed under high vacuum, H2O and 10% NaHCO3 aq. solution were added to the residue, and the compound was extracted with EtOAc. After drying over Na2SO4, filtration and concentration under vacuum, the crude product was purified by flash chromatography (50 g SiO2—NH2 cartridge; eluent: CH2Cl2/MeOH 95:05). More product was isolated from the aqueous phase by full evaporation and a second chromatography. White solid (971 mg, 74%).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH:23]1([NH:27][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCC3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (100 mg, 0.32 mmol) in DMSO (1 mL) in was added cyclobutanamine (100 mg, 1.41 mmol) and DIEA (110 mg, 0.85 mmol). The resulting solution was stirred for 2 hours at 70° C., and then quenched by the addition of water (50 mL) and extracted with dichloromethane (4×20 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2%-10% ethyl acetate in petroleum ether) to afford methyl 3-(cyclobutylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (67 mg, 58%)
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([C:25]#[N:26])=[C:20]([Cl:27])[CH:19]=3)=[N:14]2)=[O:9])[CH:4]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C.CCOC(C)=O>[N:29]1([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[C:22]([F:24])[C:21]([C:25]#[N:26])=[C:20]([Cl:27])[CH:19]=4)=[N:14]3)=[O:9])[CH:4]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(CBr)on1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(Cn2ccnc2)on1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 27.3 %

Procedure:
(S)-5-(Bromomethyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide (0.137 mmol, 0.064 g) was suspended in DMF (5 ml). Imidazole (2.74 mmol, 0.187 g) was added and the resulting mixture was stirred at RT for 2.5 h. The reaction mixture was heated to 60° C. for 1.5 h. The mixture was diluted with EtOAc and washed four times with water. The organic phase was dried, filtered and evaporated. The crude product was purified by preparative HPLC. 0.017 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.15 (d, 3H), 4.31 (d, 2H), 4.37-4.50 (m, 1H), 5.50 (s, 2H), 6.63 (s, 1H), 6.94 (s, 1H), 6.99 (d, 1H), 7.22-7.24 (m, 1H), 7.76 (s, 1H), 7.83 (d, 1H), 7.84-7.88 (m, 1H), 7.96 (s, 1H), 8.81 (d, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1.[O:18]1[CH2:21][CH:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:17][N:14]1[C:15](=[O:16])[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[N:25]2[CH2:26][CH2:27][N:22]([CH:20]3[CH2:21][O:18][CH2:19]3)[CH2:23][CH2:24]2)[N:12]=[N:13]1
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2F)c1=O
Reactant: C1CN(C2COC2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnn(-c2cc([N+](=O)[O-])ccc2N2CCN(C3COC3)CC2)c1=O
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 1-(2-fluoro-5-nitrophenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (1.1 g, 1.0 eq, 4.5 mmol) (see, e.g., WO 2011/068898), 1-(oxetan-3-yl)piperazine (0.64 g, 1.0 eq, 4.5 mmol) was dissolved in annhydrous DMF (100 mL) and stirred at room temperature. K2CO3 (1.9 g, 3.0 eq, 13.5 mmol) was added to the above solution and the heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL) and partitioned with H2O (50 mL). The layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to leave a crude solid. Purification of the crude solid by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 1:9 to 1:1) as eluent gave the product in 50% yield.