Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.O>C1(C)C=CC=CC=1>[CH3:12][N:2]([CH3:1])[C:3](=[O:11])[CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:16][CH2:15][N:14]([CH3:18])[CH3:13]
Reactant: CN(C)CCCl
Reactant: CN(C)C(=O)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCC(C(=O)N(C)C)c1ccccc1
Yield: 76.8 %

Procedure:
To a mechanically-stirred, refluxing suspension of 5.85 g (0.15 mol) of NaNH2 in 150 ml of toluene, was added dropwise under N2, 50 ml of a toluene solution consisting of 16.3 g (0.1 mol) of N,N-dimethyl-phenylacetamide (prepared by reaction of phenylacetyl chloride and N,N-dimethylamine in CH2Cl2 solvent) in toluene, and the mixture was stirred at reflux for 4 hr. Then, 16.5 g (0.15 mol) of 2-(dimethylamino)ethyl chloride in 100 ml of toluene was added dropwise. The mixture was refluxed for 6 hr and then stirred at RT for 16 hr. Water (150 ml) was added to the mixture, and then the organic layer was separated and extracted with 1N HCl. The acid extract was basified in the cold with 2.5N NaOH and the basic solution extracted with Et2O. The ether extract was dried (Na2SO4), concentrated, and distilled to afford 18 g (76.8%) of N,N-dimethyl-4-dimethylamino-2-phenylbutanamide as a colorless oil, bp 108°-110°/0.2 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(O)(C(F)(F)F)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(OC)c(OC)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc(Nc2ncccc2-c2nc(C)nc(N)n2)cc1OC
Temperature: 25 °C
Yield: 11.1 %

Procedure:
A solution of 4-(2-(3,4-dimethoxyphenylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.255 g, 0.441 mmol) in TFA (8.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature, the mixture was concentrated, the crude residue was treated with 2M NH3 in MeOH and dry-packed with silica gel. Purification using an ISCO Combiflash Companion (12 g column; 1-25% MeOH in DCM over 30 min; product eluted with 11% MeOH) gave material of insufficient purity for testing. The residue was suspended in MeOH and the solid was removed by filtration to give 4-(2-(3,4-dimethoxyphenylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.017 g, 0.049 mmol, 11.12% yield) as a brown amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 11.77 (s, 1H); 8.75 (dd, J=7.7, 1.9 Hz, 1H); 8.31 (dd, J=4.5, 2.0 Hz, 1H); 7.79 (br. s., 1H); 7.70 (br. s., 1H); 7.47 (d, J=2.3 Hz, 1H); 7.30 (dd, J=8.7, 2.4 Hz, 1H); 6.91 (d, J=8.8 Hz, 1H); 6.84 (dd, J=7.8, 4.7 Hz, 1H); 3.79 (s, 3H); 3.74 (s, 3H); 2.44 (s, 3H). m/z (ESI, +ve ion) 339.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O-:11].[Na+]>CO>[NH2:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1N

Procedure:
A mixture of 5-amino-2,4-dichloropyrimidine (0.32 g) (obtained as described in Chem. Pharm. Bull., (JAPAN), 1958, 6, 343-346) and a solution of sodium methoxide in methanol (from sodium (0.05 g) and methanol (25 ml)) was heated at reflux for 15 minutes and allowed to cool. Volatile material was removed by evaporation and a small volume of water added. The mixture was extracted twice with ether and the combined extracts were dried (MgSO4) and evaporated to give 5-amino-2-chloro-4-methoxypyrimidine (0.2 g) as an oil; 1H NMR (d6 -DMSO): 3.92 (s, 3H), 5.25 (s, 2H), 7.72 (s, 1H); mass spectrum (+ve CI): 160 (M+H)+.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][C:5]1=O)(=O)[CH3:2].[CH3:12][CH:13]([C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[C:25]([CH:27]=1)[OH:26])[CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>C(O)(=O)C>[CH3:12][CH:13]([C:21]1[CH:27]=[C:25]([OH:26])[C:24]2[CH:1]([CH3:2])[C:4]3[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][C:5]=3[O:28][C:23]=2[CH:22]=1)[CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CC(=O)C1CCC(C)CC1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C
Reaction time: 20 h

Procedure:
A solution of 3.6 g. of 2-acetyl-5 -methylcyclohexanone and 5.6 g. of 5-(1,2-dimethylheptyl)resorcinol in 150 ml. of acetic acid is cooled to 15° and saturated with hydrogen chloride gas. The solution is allowed to warm to 25°, stirred for 20 hours and then heated for one hour on a steam bath. The reaction mixture is concentrated in vacuo, water is added and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water, dried (MgSO4) and concentrated to give a residue which is distilled five times, b.p. 195°-200° (0.025 mm.). The distillate is chromatographed on silica gel with benzene as eluant. The second fraction is collected and distilled to give the title compound, b.p. 190°-195° (0.05 mm.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].[CH3:32][C:33]1[N:41]=[C:40]([Cl:42])[CH:39]=[C:38]([CH3:43])[C:34]=1[C:35](O)=[O:36].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:42][C:40]1[CH:39]=[C:38]([CH3:43])[C:34]([C:35]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH2:8][CH2:7]2)[CH3:5])=[O:36])=[C:33]([CH3:32])[N:41]=1
Reactant: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(Cl)nc3C)CC2)cc1
Reaction time: 8 h
Yield: 22.8 %

Procedure:
Following General Procedure C: To a solution of [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(2-methoxy-ethoxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amine (130 mg, 0.31 mmol) and 2,4-dimethyl-6-chloronicotinic acid (68 mg, 0.31 mmol) in DMF (4 mL) was added DIPEA (0.8 mL), HOBT (75 mg, 0.56 mmol) and EDCI (89 mg, 0.46 mmol) and the reaction stirred overnight. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH,) gave 42 mg (23%) of the title compound as a white solid: 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6 Hz) 1.07-1.32 (m, 2H), 1.53-1.61 (m, 1H), 1.83-1.91 (m, 3H), 2.29 (s, 3H), 2.34 (s, 3H), 2.48 (s, 3H, 2.76-2.91 (m, 3H), 3.26-3.39 (m, 3H), 3.43 (s, 3H), 3.68-3.71 (m, 2H), 3.73-3.82 (m, 1H), 4.01-4.04 (m, 4H), 6.64 (d, 2H, J=9 Hz), 6.76 (d, 2H, J=9 Hz), 6.98 (s, 1H), 7.03 (d, 1H, J=6 Hz), 7.97 (br s, 1H), 8.26 (s, 1H), 8.29 (d, 1H, J=6 Hz). 13C NMR (CDCl3) δ 13.60, 19.19, 22.52, 29.68, 30.58, 31.80, 39.70, 44.36, 47.79, 59.57, 60.04, 68.06, 71.53, 115.72, 120.29, 122.88, 125.50, 148.34, 149.57. ES-MS m/z 594 (M+H). Anal. Calcd. for C33H44N5ClO3.0.2CH2Cl2: C, 65.24; H, 7.32; N, 11.46. Found: C, 64.88; H, 7.36; N, 11.54.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH:11]=[C:10]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=5)[NH:9][C:8]4=[O:18])[CH2:5][CH2:6]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: O=c1[nH]c(-c2ccccn2)cn1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(n3cc(-c4ccccn4)[nH]c3=O)CC2)C1=O
Yield: 37 %

Procedure:
Title compound was prepared from 1-(piperidin-4-yl)-4-(pyridine-2-yl)-1H-imidazol-2(3H)-one in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 37% yield. MS m/e (M+H)+=590.2. 1H NMR (500 MHz, DMSO-D6): δ=13.54 (s, 1H), 10.69 (d, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 7.74 (s, 1H), 7.54 (d, J=8.24, 1H), 7.33 (d, J=4.88, 1H), 7.25 (s, 1H), 7.15 (dd, J1=6.71, J2=5.19, 1H), 5.37 (d, J=17.09, 1H), 4.63 (d, J=15.87, 1H), 4.50 (s, 1H), 4.12 (m, 2H), 3.87 (m, 1H), 3.56 (dd, J1=28.69, J2=13.43, 1H), 3.18 (t, J=$$ 13.73, 1H), 3.10 (d, J=14.65, 1H), 3.01 (m, 2H), 2.88 (t, J=15.26, 1H), 2.66 (m, 1H), 2.35 (d, J=14.95, 1H), 1.84 (m, 3H), 1.57 (m, 1H), 0.73 (d, J=16.17, 9H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=2[O:21][CH3:22])[N:10]=1.Cl[C:25]1[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=1.CN(C)C=O.[H-].[Na+]>O>[C:31]([C:30]1[C:25]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:23])=[C:14]([O:21][CH3:22])[CH:15]=2)=[N:26][CH:27]=[CH:28][CH:29]=1)#[N:32]
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2ncccc2C#N)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
To a mixture of [4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxyphenyl]methanol (5.00 g), 2-chloro-3-cyanopyridine (2.65 g) and N,N-dimethylformamide (150 mL) was added sodium hydride (60%, oil, 0.70 g) at room temperature and the mixture was stirred for 15 hrs. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give crystals (6.60 g, yield 99%) of 3-cyano-2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]pyridine. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[O-]S([O-])(=O)=O.[Mg+2].[CH:14]1[C:19]([CH:20]=O)=[CH:18][C:17]2[O:22][CH2:23][O:24][C:16]=2[CH:15]=1>C(Cl)(Cl)Cl.O>[CH2:23]1[O:24][C:16]2[CH:15]=[CH:14][C:19]([CH:20]=[N:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[CH:18][C:17]=2[O:22]1
Reactant: COC(CN)OC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(CN=Cc1ccc2c(c1)OCO2)OC
Temperature: 25 °C
Yield: 100 %

Procedure:
Aminoacetaldehyde dimethylacetal (7.10 g, 0.0666 mol) was dissolved in chloroform (50 mL) and MgSO4 (12 g) was added. Then piperonal (10b, 10.10 g, 0.0666 mol) was added and the mixture was stirred at room temperature. After 24 h there still was unreacted piperonal in the reaction mixture and more amine (6.00 g) was added. The reaction mixture was stirred again at room temperature for 24 h and since there still was some piperonal present more amine (6.00 g) was added again. After stirring the reaction mixture for another 24 h at room temperature the imine was isolated. The reaction mixture was diluted with water (300 mL) and the organic layer was washed with water 200 mL×2, brine (200 mL) dried Na2SO4 and concentrated to provide the pure imine as a yellow oil (15.80 g, 100%). 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 7.33 (s, 1H), 7.07 (d, J=8.10 Hz, 1H), 6.78 (d, J=8.10 Hz, 1H), 5.96 (s, 2H), 4.62 (t, J=5.4 Hz, 1H), 3.70 (d, J=4.2, 2H), 3.83 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([SH:9])[N:4]=1.[OH-].[Na+].CI.[CH2:16](Cl)Cl>C1COCC1>[CH3:16][S:9][C:5]1[N:4]=[C:3]([C:2]([F:10])([F:1])[F:11])[CH:8]=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccnc(S)n1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(trifluoromethyl)pyrimidine-2-thiol (1.08 g, 6.0 mmol) in THF (40 mL) was added 1N NaOH (10 mL), followed by the addition of MeI (0.8 mL). The reaction mixture was stirred at room temperature overnight, followed by addition of CH2Cl2. The organic layer was washed with saturated NaHCO3, H2O, and saturated NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes: EtOAc=1:10) to give 2-(methylthio)-4-(trifluoromethyl)pyrimidine as colorless oil (0.6 g). This colorless oil was dissolved in CH2Cl2, and to the solution mCPBA (1.8 g) was added. The resulting mixture was stirred at room temperature for 3 h. To the reaction mixture saturated Na2SO4 (10 mL) was added, followed by the addition of saturated Na2CO3. The aqueous portion was extracted with CH2Cl2 twice and the organic portions were dried over Na2SO4, filtered, and concentrated to give 2-(methylsulfonyl)-4-(trifluoromethyl)pyrimidine as white solids (0.64 g, 46% yield for two steps,). LC-MS RT=1.19 min, [M+Na] 249.06 (LCMS Method 1).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:9][CH:8]=2)[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C(=O)O)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(OCc3ccccc3)c2C(=O)O)=C(C)C1=O
Yield: 62.6 %

Procedure:
6-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (106 mg, 0.2345 mmol) was dissolved in a mixed solution of acetonitrile (6 ml) and water (2 ml) and after adding thereto CAN (321 mg, 0.5857 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (62 mg, 0.1469 mmol, 64%).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][CH:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[NH:9]1
Reactant: O=c1[nH]c2c(n1-c1ccccc1)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: ClC1NC2=C(CCCC2)N1c1ccccc1
Yield: 32.2 %

Procedure:
A mixture of 2.3 g (0.0107 mol) of 1-phenyl-4,5,6,7-tetrahydro-2H-benzimidazol-2-one and 30 ml of POCl3 is stirred under reflux for 6 hours. The excess POCl3 is evaporated under vacuum and the residue is hydrolyzed with water and concentrated ammonium hydroxide. The mixture is extracted twice with methylene chloride, evaporated and the residue is purified by flash chromatography on silica with an 80:20 heptane/ethyl acetate eluent. 0.8 g of product is recovered. Yield=32.2%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (9.2 g) in dichloromethane (170 ml), stirring at 0° C. was added methane sulphonyl chloride (5.33 ml) and triethylamine (0.24 ml). The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was partitioned between chloroform and water. The combined organics were washed with brine and dried (MgSO4). The solvent was removed in vacuo to yield 14 g of 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[N:21][C:20](Br)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[C:25]([Cu])#[N:26]>CN1C(=O)CCC1>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[N:21][C:20]([C:25]#[N:26])=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(C#N)cn2)c2c1C[C@H]1C[C@@H]21
Temperature: 200 °C

Procedure:
A heterogeneous mixture of (1aR,5aR)-2-(5-bromo-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (40 mg, 0.10 mmol) and cyanocopper (13.7 mg, 0.15 mmol) in NMP (1.0 mL) in a heavy walled tube was heated at 200° C. under microwave irradiation for 2 h. The reaction was filtered and purified by preparative HPLC to give the title compound. LCMS m/z=339.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46 (td, J=4.7 and 3.4 Hz, 1H), 1.29 (td, J=8.0 and 4.7 Hz, 1H), 1.42 (s, 3H), 1.43 (s, 3H), 2.30-2.37 (m, 1H), 2.71-2.77 (m, 1H), 2.92 (d, J=17.0 Hz, 1H), 3.01 (dd, J=16.8 and 6.2 Hz, 1H), 3.71 (s, 2H), 4.29 (s, 1H), 6.90 (s, 1H), 8.72 (d, J=1.4 Hz, 1H), 9.33 (d, J=1.4 Hz, 1H).
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[P:14]([O:19]C)([O:17][CH3:18])[O:15][CH3:16].BrCCN1C(=O)C2=CC=CC=C2C1=O.P(OCC)(OCC)OCC>>[C:7]1(=[O:8])[N:3]([CH2:2][P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]12
Reactant: COP(OC)OC
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: CCOP(OCC)OCC
Agent: O=C1c2ccccc2C(=O)N1CCBr
Product: COP(=O)(CN1C(=O)c2ccccc2C1=O)OC

Procedure:
Reaction of N-bromomethylphthalimide with trimethyl phosphite as described in Example 18 for N-(2-bromoethyl)-phthalimide and triethyl phosphite gives dimethyl phthalimidomethylphosphonate.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][C:18]([NH:31]C(OC(C)(C)C)=O)([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>CO>[ClH:30].[ClH:1].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][CH2:21][C:18]2([NH2:31])[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NC1(COCc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(COCc2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
A 4M solution of HCl in dioxane (0.68 ml, 2.7 mmol) was added dropwise to a solution of 4-tert-butoxycarbonylamino-4-(4-chloro-benzyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (12 mg, 0.028 mmol) in methanol (1 mL). The solution was stirred at rt for 17 h. The solvents were removed by evaporation to give 4-(4-chloro-benzyloxymethyl)-piperidin-4-ylamine dihydrochloride (9.2 mg, 0.028 mmol, 100%) that was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][N:15]=[C:16]([C:20](=[O:22])[CH3:21])[C:17](=[O:19])[CH3:18])([CH3:6])([CH3:5])[CH3:4].[CH2:23]([O:30][CH2:31][C:32](Cl)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1>[CH2:23]([O:30][CH2:31][C:32](=[O:33])[CH2:21][C:20](=[O:22])[C:16](=[N:15][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][C:3]([CH3:6])([CH3:4])[CH3:5])[C:17](=[O:19])[CH3:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CC(=O)C(=NNc1ccccc1OC(C)(C)C)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(=NNc1ccccc1OC(C)(C)C)C(=O)CC(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
NaH (4.28 g) was suspended in THF (30 mL), and a solution of 3-[(2-tert-butoxyphenyl)hydrazono]pentane-2,4-dione (7.47 g) in THF (100 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 40 min, a solution of (benzyloxy)acetylchloride (5.55 mL) in THF (20 mL) was added at 0° C., and the mixture was stirred at 0° C. for 5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.58 g).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)N>>[CH3:24][NH:23][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:26]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: Cc1cc(NN)ccn1
Reactant: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc(C)c3)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzenesulfonamide (A-31) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=423.1 (M+H)+
Reaction SMILES: O[CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:15][CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: O=c1onc2n1C(CO)CCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1onc2n1C(CBr)CCCC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the product of Example 5 in dichloromethane was added carbon tetrabromide (460 mg, 1.3 mmol). This solution was cooled in an ice bath and stirred for minutes. Triphenylphosphine (437 mg, 1.6 mmol) was added to the solution and stirring was continued for 5 minutes at 0° C. before allowing it to warm slowly to room temperature. The solvent was removed under reduced pressure. The residue was placed on a filter and washed three times with ether. The filtrate solvent was then removed under reduced pressure to yield the title compound.
Reaction SMILES: COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)NN=2)C=CC=1OC.BrC([C:25]1[C:33]2[N:32]=[N:31][NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)C.[CH2:34]([N:41]1[N:50]=[C:49]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([O:59][CH3:60])[CH:52]=2)[C@H:48]2[C@H:43]([CH2:44][CH2:45][CH2:46][CH2:47]2)[C:42]1=[O:61])C1C=CC=CC=1.C([O-])C.[Na+]>>[N:30]1([CH2:34][N:41]2[N:50]=[C:49]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([O:59][CH3:60])[CH:52]=3)[C@H:48]3[C@H:43]([CH2:44][CH2:45][CH2:46][CH2:47]3)[C:42]2=[O:61])[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:33]=2[N:32]=[N:31]1
Reactant: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: CC(Br)c1cccc2[nH]nnc12
Agent: CC[O-]
Agent: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: [Na+]
Product: COc1ccc(C2=NN(Cn3nnc4ccccc43)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 1-bromoethylbenzotriazole as described for compound 78, using sodium ethanolate instead of sodium hydride. Purified by chromatography [ethyl acetate:petroleum ether (60°-95° C.)/1:2]. Crystallized from methanol. M.p. 173°-178° C.