Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=3)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30][NH2:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:31][CH3:30])[CH:23]=3)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(c1cccc(C=O)c1)C1(c2ccc(Cl)cc2)CCC1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNCc1cccc(C(CNC(=O)OC(C)(C)C)C2(c3ccc(Cl)cc3)CCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl {2-[1-(4-chlorophenyl)cyclobutyl]-2-(3-formylphenyl)ethyl}carbamate (0.19 g, 0.459 mmol) was dissolved in dichloromethane and methylamine (1.15 ml, 2.295 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.146 g, 0.689 mmol) was added. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with sodium hydroxide (1 N) and extracted with ethyl acetate. The combined extracts were dried (magnesium sulfate), concentrated in vacuo and the crude product purified by flash chromatography (silica, dichloromethane, methanol). Yield: 0.11 g (0.256 mmol, 56%)
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]1[N:12]1[CH:20]=[N:19][C:18]2[C:13]1=[N:14][CH:15]=[N:16][C:17]=2[NH2:21].O.[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38](ON3C(=O)CCC3=O)=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:1][C@@H:2]3[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]3[N:12]3[CH:20]=[N:19][C:18]4[C:13]3=[N:14][CH:15]=[N:16][C:17]=4[NH2:21])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To 0.69 g (2.33 mmol) of 9-(2-amino-2-deoxy-β-D-glucopyranosyl)adenine was added 3.45 mL of H2O. To this solution was added a 28 mL 1,4-dioxane solution of 0.94 g (2.80 mmol) of N-(9-fluorenylmethoxycarbonyloxy)succinimide. This resulted in a cloudy mixture. To this system was added 0.13 g (1.50 mmol) of NaHCO3. This mixture was stirred for 12 h at room temperature. At this time, TLC indicated the consumption of starting material and the mixture was concentrated in vacuo to a dry residue. This residue was stirred for 18 h in 250 mL of Et2O and 250 ml of H2O. The suspension was then filtered and the solid dried in a vacuum oven for 2 days. Thus was obtained 1.0 g (82%) of the desired 9-[2-deoxy-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]-amino]-β-D-glucopyranosyl]adenine 1H NMR: (DMSO-d6): adenine aromatic 8.19 (s, 1H), adenine aromatic 8.17 (s, 1H), anomeric H-1 6.60 (d, 1H), Fmoc-methine 4.17 (m, 1H). FAB-MS: m/z 519 for (M+1)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.[F-].[K+]>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.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) and 4-fluorophenylboronic acid (4.6 g, 32 mmol) in 4:1 toluene:water (100 mL) were added potassium fluoride (3.8 g, 66 mmol) and Pd(PPh3)4 (2.5 g, 2.2 mmol). The resulting mixture was stirred at reflux for 12 h. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the crude residue by silica gel chromatography gave 4′-fluorobiphenyl-4-carbonitrile (4.2 g) as a colorless solid. 1H NMR (400 MHz, CD3OD) δ 7.69 (s, 4H), 7.63-7.60 (m, 2H), 7.15-7.10 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH2:22][C:23]([N:37]2[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]2)=[O:24])=[O:20])=[CH:26][CH:27]=1)(=[O:14])=[O:13]
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2Cl)cc1
Reactant: OC1CCNCC1
Product: O=C(NCC(=O)N1CCC(O)CC1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2Cl)cc1

Procedure:
The title compound was prepared from {4-[2-(2-chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid and 4-hydroxypiperidine according to the method described in Example 1.1/f. MS (EI) 562.3 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[CH3:9][C:10]1[N:11]([C:19]2[NH:27][C:26](Cl)=[N:25][C:24]3[C:20]=2[N:21]=[CH:22][N:23]=3)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>>[CH3:9][C:10]1[N:11]([C:19]2[N:27]=[C:26]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Cc1cc2ccccc2n1-c1[nH]c(Cl)nc2ncnc1-2
Product: Cc1cc2ccccc2n1-c1nc(N[C@H]2CC[C@H](N)CC2)nc2[nH]cnc12
Temperature: 140 °C

Procedure:
The same procedure as in stage 2 of Example 1 is carried out, starting from 684 mg of trans-1,4-diaminocyclohexane and 166 mg of the product obtained in stage 2 above, and the mixture is heated at 140° C. for 6 hours. Purification is carried out on silica with MeOH—NH4OH: 98-2 for eluent, and 51 mg of expected product are thus obtained, in the form of beige-colored crystals.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1>ClCCl>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(NC(=O)c2cc(NC3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and N-(4-aminophenyl)methanesulfonamide (prepared according to the method described by Lee et al. in Bioorg. Med. Chem. Lett. 2005, 15, 4136-4142), the title compound was obtained as a white solid after trituration in dichloromethane.
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH:10]=1)([O-])=O.N.[H][H]>[Ni].CO>[NH2:1][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CCOC(=O)N1CC=C(C[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOC(=O)N1CCC(CN)CC1
Yield: 98.9 %

Procedure:
A mixture of 41 parts of ethyl 3,6-dihydro-4-(nitromethyl)-1(2H)pyridinecarboxylate and 400 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at room temperature with 6 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 35 parts (98.9%) of ethyl 4-(aminomethyl)-1-piperidinecarboxylate (intermediate 4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(S)cc1
Reactant: Fc1ccc(Br)c(I)c1
Product: Cc1ccc(Sc2cc(F)ccc2Br)cc1

Procedure:
Prepared from 4-methyl-benzenethiol and 1-bromo-4-fluoro-2-iodo-benzene.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22]C(=O)OC(C)(C)C)[N:21]=2)[N:18]=1)=[O:7].Cl.C(OCC)(=O)C>CO>[NH2:22][C:20]1[N:21]=[C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:33]=[CH:34][CH:35]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:4]=4)[CH:32]=[CH:31][CH:30]=3)=[N:18][N:17]2[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.2 %

Procedure:
A mixture of tert-butyl [6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate (2.37 g, 4.62 mmol), 4N hydrochloric acid-ethyl acetate solution (50 mL) and methanol (50 mL) was stirred at room temperature for 6 hr. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone→ethyl acetate/methanol=4:1) to give the title compound (1.57 g, 82%) as a green solid.
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:5]=2[CH:4]=[C:3]([CH2:15]O)[N:2]=1.ClCCCl.S(Br)([Br:23])=O>C(Cl)(Cl)Cl>[Br:23][CH2:15][C:3]1[N:2]=[N:1][C:6]2[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:5]=2[CH:4]=1
Reactant: O=S(Br)Br
Reactant: OCc1cc2c(nn1)Oc1ccccc1O2
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: BrCc1cc2c(nn1)Oc1ccccc1O2
Yield: 76.5 %

Procedure:
To [1,4]benzodioxino[2,3-c]pyridazin-3-ylmethanol (8.1 g) was added 1,2-dichloroethane (80 ml) and the mixture was stirred. Thionyl bromide (38.9 g) was added, and the mixture was stirred with heating under reflux for 2 hr. The mixture was diluted with chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was washed with diethyl ether to give 3-(bromomethyl)[1,4]benzodioxino[2,3-c]pyridazine (8.0 g).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=3)[C:16]([NH:18][C:19]3[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([O:24][CH3:25])=[O:23])=[O:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1>[CH3:30][C:20]1[C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:31]=[C:11]([N:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[CH:12]=[CH:13][C:14]=2[CH3:32])=[C:28]([CH3:29])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC4(CC3)OCCO4)ccc2C)c1C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(=O)CC3)ccc2C)c1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 0 %

Procedure:
To a solution of methyl 3-[[5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-benzoyl]amino]-2,4-dimethyl-benzoate (250 mg, 570.09 moles) in THF (2 ml) is added 4M HCl (1 ml) and stirred at ambient temperature. The mixture is concentrated under reduced pressure and re-dissolved in acetone (5 ml) followed by the addition of 5N HCl (1 ml). After 22 hours at 60° C., the mixture is cooled to ambient temperature and diluted with 2M NaOH to pH 6 and extracted twice with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 0-50% ethyl acetate in hexane to afford the title compound as an off-white foam (0.12 g, 53.36%). Mass spectrum (m/z): 395.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])([O-])=O.C([O-])=O.[NH4+]>C1COCC1.CO>[F:13][C:12]([F:14])([F:15])[CH2:11][NH:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1NCC(F)(F)F
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccccc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (2-nitro-phenyl)-(2,2,2-trifluoro-ethyl)-amin (2.16 g, 9.8 mmol) in THF (6 mL) and MeOH (24 mL) at 0° C. was added ammonium formate (2.47 g, 39.2 mmol). The resulting mixture was purged with nitrogen, then 10% Pd/C (57 mg) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 5 h. The resulting mixture was filtered over CELITE®, washing with EtOAc. Removal of the solvent in vacuo yield N-(2,2,2-trifluoro-ethyl)-benzene-1,2-diamine, which was used in the next step without further purification. MS 191 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26]Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:26][C:9]1[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][C:10]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)nc1-c1ccccc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(-c2ccccc2)nc(-c2ccncc2)c1Br
Reaction time: 0.67 h
Yield: 98.7 %

Procedure:
To a solution of the product of Step 1 (15 g, 42.6 mmol) in dichloromethane (300 ml) at room temperature was added bromine (6.81 g, 2.38 ml, 46.5 mmol) followed by a saturated solution of sodium carbonate (150 ml). The mixture was stirred for 40 minutes before being separated and the organic layer washed successively with water and brine. The organic layer was then dried (magnesium sulphate) and concentrated in vacuo to give the title compound (18.1 g, 99%) as a brown viscous oil which was used without further purification; MS(AP+) m/e 431/433 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:10][C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3]1.C(O)C.Cl.[OH:15][NH2:16].[OH-].[Na+]>O>[OH:15][N:16]=[C:2]1[CH2:10][C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3]1
Reactant: NO
Reactant: O=C1C[C@H]2CC=CC[C@H]2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=C1C[C@H]2CC=CC[C@H]2C1
Reaction time: 1 h

Procedure:
To a mixed solution of 8-oxo-cis-bicyclo[4,3,0]nona-3-ene (10 g), ethyl alcohol (100 ml), water (20 ml) and hydroxyamine hydrochloride (20 g), was added sodium hydroxide (37 g) at room temperature. After being stirred for one hour, the reaction mixture was poured into water. The crystals were gathered by filtration and washed with water. After drying, there was obtained 8-hydroxyimino-cis-bicyclo[4,3,0]nona-3-ene.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:27]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.42 g of benzylpiperazine are dissolved in 35 ml of methylene chloride and there are added thereto 2.1 g of triethylamine and then, dropwise and while cooling with ice, 3.4 g of 3-methoxybenzoyl chloride in 30 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature and then washed with H2O. After being dried over sodium sulphate, the solution is concentrated to dryness by evaporation in vacuo. The oily 1-benzyl-4-(3-methoxybenzoyl)-piperazine is dissolved in 150 ml of fine spirit and debenzylated over 0.5 g of Pd-C. When the hydrogenation is complete, the catalyst is filtered off from the mixture and the filtrate is concentrated to dryness by evaporation in vacuo. The oily N-(3-methoxybenzoyl)-piperazine so obtained is placed in a sulphonating flask with 3.8 g of p-chlorophenethyl bromide and heated to 100°. At 60° a slight exothermic reaction takes place. After 3 hours at 100° , the mixture is cooled and dissolved in 400 ml of methylene chloride, and then 2N NaOH is added thereto; the whole is extracted by shaking and the methylene chloride phase is washed twice with H2O. The organic phase is dried over Na2SO4 and concentrated to dryness by evaporation in vacuo. The oily 1-[2-(4-chlorophenyl)-ethyl]-4-(3-methoxybenzoyl)piperazine is dissolved in isopropanol, and hydrochloric acid is added thereto. After the addition of ether, the hydrochloride, which has a melting point of 230°-232°, crystallises.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:18][CH:19]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])N(C)C)[C:14]([CH3:17])([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[CH3:15][C:14]([CH3:17])([CH3:16])[CH2:13][O:18][CH:19]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)COC(OCC(C)(C)C)N1CCN(c2ccccc2)CC1

Procedure:
A solution of 4-phenylpiperazine (0.162 g, 0.001 mol) and dimethylformamide dineopentyl acetal (0.346 g, 0.0015 mol) in anhydrous chloroform (5 mL) was refluxed for 10 hours. The solvent and excess reagent were removed (100° C./1 mm) to give the product in quantitative yield.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1>[O-2].[Mn+4].[O-2].ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc2cccnc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.2 %

Procedure:
A mixture of 8.6 parts of 7-quinolinemethanol, 20 parts of manganese(IV)oxide and 130 parts of dichloromethane was stirred for 24 hours at room temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 8 parts (94.2%) of 7-quinolinecarboxaldehyde; mp. 56° C. (interm. 1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[CH3:30][N:31]([CH:33]=O)[CH3:32]>C(Cl)Cl>[C:4]([C:3]1[CH:9]=[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:12][C:2]=1[N:1]=[CH:30][N:31]([CH3:33])[CH3:32])([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N=CN(C)C
Temperature: 55 °C

Procedure:
To a stirred solution of 15.7 g (50 mmol) of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate (Pfizer patent WO 96130347) in 50 ml of DMF at 0° C. was added phosphorous oxychloride (5.6 ml, 60 mmol) during 15 m. The resulting solution was heated at 55° C. for 45 m, cooled, diluted with methylene chloride, and treated at 0° C. with 200 ml of N/1 sodium hydroxide during 2 m. The organic layer was separated and washed at 0° C. with water. The solution was dried and evaporated with added toluene present to give 18.4 g of amber oil; NMR (CDCl3) δ 3.02 (s, Me2N).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH2:15]([O:14][C:10](=[O:13])/[CH:11]=[CH:12]/[C:6]1[C:5]([NH2:9])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH3:16]
Reactant: Nc1ccc(Br)nc1I
Reactant: C=CC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1nc(Br)ccc1N
Temperature: 80 °C

Procedure:
15.5 g 6-Bromo-2-iodo-pyridin-3-ylamine, 5.9 ml ethyl acrylate, 2.72 g triphenylphosphine and 28.75 ml triethylamine were dissolved in 90 ml acetonitrile. An argon stream was bubbled through the reaction mixture for 10 minutes then 2.33 g palladium(II)acetate were added and the reaction mixture stirred at 80° C. The reaction mixture was filtered hot trough a pad of celite then the solvent was removed in vacuo. The residue was purified by chromatography on silica gel to obtain 10.2 g (E)-3-(3-Amino-6-bromo-pyridin-2-yl)-acrylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=2)[CH:7]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:23]#[C:24][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([CH:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH:10]=3)[CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1cnc2cc(C3CCOCC3)nn2c1
Product: C(#Cc1cnc2cc(C3CCOCC3)nn2c1)c1ccccc1

Procedure:
The title compound, grey solid, MS: m/e=304.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-(tetrahydro-pyran-4-yl)-pyrazolo[1,5-a]pyrimidine (example 26, step 2) and phenylacetylene.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[C:6](=[O:15])[CH2:5]1)[CH2:2][CH3:3].[Cl:16]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C1COCC1>[Cl:16][C:14]1[N:10]([CH2:9][N:7]2[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]2=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCC1CC(=O)N(Cn2cccc2)C1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCC1CC(=O)N(Cn2cccc2Cl)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one x264 (0.182 g, 0.88 mmol) is dissolved in absolute THF (3 ml). A solution of N-chlorosuccinimide (0.118 g, 1 eq) in absolute THF (1 ml) is added dropwise in a flow of argon at 0° C. The obtained solution is allowed to heat up slowly to room temperature in the cooling bath under stirring for 16 h. CCl4 (30 ml) is then added to the obtained solution. A small amount of a precipitate is filtered off, and the filtrate is evaporated. 1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one 299 is isolated from the residue by reverse-phase HPLC (eluent: acetonitrile/water).
Reaction SMILES: C1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)CCCCC=1.[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.N1CCOCC1>C1CCCCC1>[CH3:13][C:14]1([CH3:21])[CH2:19][CH2:18][C:17]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:16][CH2:15]1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CC1(C)CCC(=O)CC1
Solvent: C1COCCN1
Solvent: C1CCCCC1
Product: CC1(C)CC=C(N2CCOCC2)CC1

Procedure:
Compound III″ (brown liquid) is obtained quantitatively according to Example 1, from 4,4-dimethylcyclohexanone (350.03 g, 2.76 mol), morpholine (327.01 g, 3.75 mol) and cyclohexane (330 mL).