Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([NH:20][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCc1ccccc1
Solvent: CCO
Product: OC[C@H]1O[C@@H](NCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 48 h

Procedure:
50 g of D-glucose were dissolved in 1,000 ml of hot ethanol and, after addition of 89 g of benzylamine, the mixture was left at room temperature for 48 hours. It was then cooled with ice and the product was precipitated with petroleum ether. The product was filtered off with suction, washed with ether and dried in vacuo. 1H-NMR in CD3OD: δ=7.33, broad singlet, phenyl-H.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH:14]=O)[N:10]=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:16][O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:19])/[CH:20]=[CH:14]/[C:13]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=Cc1cc2ncccc2cc1[N+](=O)[O-]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1cc2ncccc2cc1[N+](=O)[O-]
Yield: 59.6 %

Procedure:
6-Nitroquinolin-7-carbaldehyde (920 mg; 4.55 mmol) in toluene (46 ml) and (methoxycarbonylmethylen)triphenylphosphoran (1.67 g; 5.0 mmol) were refluxed for 1 h. The title compound crystallised upon cooling and was filtered off. Recrystallisation from hot EtOAc (250 ml) gave pure title compound (700 mg). The mother liquor was purified via chromatography (SiO2; acetone/hexanes 30/70) to yield a further batch of pure title compound (300 mg). Total yield: 1 g; 85%.
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.[O-:8][N+:9]1[C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:13]=2[N:12]=[C:11]([CH2:22][CH2:23][CH:24]=O)[N:10]=1)[CH2:19][CH2:18][CH2:17]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[CH3:2][O:3][CH:4]1[CH2:7][N:6]([CH2:24][CH2:23][CH2:22][C:11]2[N:10]=[N+:9]([O-:8])[C:14]3[CH:15]=[C:16]4[C:20]([CH2:19][CH2:18][CH2:17]4)=[CH:21][C:13]=3[N:12]=2)[CH2:5]1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: COC1CNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC1CN(CCCc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
3-Azetidinyl methyl ether hydrochloride (275) (MacKenzie et al., PCT Int Appl. WO 9605193, 1996) (0.60 g, 4.9 mmol) was added to a stirred solution of propanal 75 (1.2 g, 4.9 mmol) in MeOH (100 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 82 (930 mg, 60%) as a yellow oil: 1H NMR δ 8.24 (s, 1H, H-9), 7.74 (s, 1H, H-5), 4.27-4.39 (m, 3H, CH2N, CHO), 3.49-3.53 (m, 2H, CH2N), 3.30 (s, 3H, OCH3), 3.21-3.27 (m, 2H, CH2N), 3.09-3.16 (m, 4H, H-6, H-8), 3.05 (t, J=7.2 Hz, 2H, CH2), 2.14-2.26 (m, 4H, H-7, CH2); 13C NMR δ 163.9, 155.1, 149.3, 147.3, 132.3, 122.7, 144.2, 68.3, 60.9, 58.7, 56.6, 56.5, 33.5, 33.1, 32.8, 25.7, 23.8; HRMS calcd for C17H22N4O2 (M+) m/z 314.1743, found 314.1742.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[Cl:16][C:17]1[N:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=1>>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]([F:15])[C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=2)=[O:26])=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:18]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: O=C(O)C=Cc1cnc(Cl)cc1C(F)(F)F
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2cnc(Cl)cc2C(F)(F)F)cc1F
Yield: 68.1 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (56 mg, 0.22 mmol) was reacted with 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (54 mg, 1.0 eq) to give 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-N-(5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (66 mg, 65.7%) after purification by column chromatography (Hex EtOAc=3/2).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Br.[C:17](O)(=O)C>O>[O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:17])=[O:6]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: COC(=O)CCC(=O)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
A mixture of the compound from Step 1 (77.3 g), 48% HBr (310 ml), and acetic acid (620 ml) was heated under reflux for 18 hours. The resulting mixture was cooled to room temperature and poured into 3 liters of water. The resulting solution was extracted with ethyl acetate (3×500 ml). The combined organic layers were washed with water (4×200 ml), dried over Na2SO4, the solvents were removed by evaporation and the residue was dissolved in 10% HCl/methanol (500 ml). After 10 hours at room temperature the volatile components were removed by evaporation in vacuo. The resulting residue was triturated with hexane to yield the title compound, m.p. 115°-116°.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3[C:24]4[N:25]([CH2:41][CH2:42][N:43]=4)[C:26]([NH:32][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=4)=[N:27][C:28]=3[C:29]=2[O:30][CH3:31])[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[OH:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3[C:24]4[N:25]([CH2:41][CH2:42][N:43]=4)[C:26]([NH:32][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=4)=[N:27][C:28]=3[C:29]=2[O:30][CH3:31])[CH2:11]1
Reactant: COc1c(OCCCN2CCOC(CO[Si](C)(C)C(C)(C)C)C2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(OCCCN2CCOC(CO)C2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
N-(8-{3-[2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (260 mg, 0.43 mmol) was suspended in THF (2 mL) and treated with a solution of tetra-n-butylammonium fluoride (1N, 0.64 mL, 0.64 mmol) in THF. The resulting mixture was stirred at rt for 4 h and was then diluted with water and extracted with 20% isopropanol/80% chloroform, dried (MgSO4) and concentrated under reduced pressure. The residue was then triturated with methanol and filtered to give the product as a solid (100 mg, 47%): HPLC MS RT=0.19 min, MH+=495.2; 1H NMR (DMSO-d6) δ: 12.7 (1H, s), 9.33 (1H, dd), 8.73 (1H, dd), 8.46 (1H, dt), 7.60 (1H, d), 7.54-7.49 (1H, m), 7.06 (1H, d) 4.66 (1H, t), 4.20-4.09 (4H, m), 4.07-3.98 (2H, m) 3.93 (3H, s), 3.76 (1H, br d), 3.48 (1H, td), 3.42-3.26 (4H, m), 2.83 (1H, d), 2.70 (1H, d), 2.47 (2H, t), 2.03-1.91 (3H, m).
Reaction SMILES: [CH:1]1([C:4](=[O:21])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([NH:18][CH3:19])[C:9]=2[CH3:20])=[O:7])[CH2:3][CH2:2]1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C(Cl)Cl>[CH:1]1([C:4](=[O:21])[C:5](=[CH:24][N:25]([CH3:27])[CH3:26])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([NH:18][CH3:19])[C:9]=2[CH3:20])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: CNc1c(S(C)(=O)=O)ccc(C(=O)CC(=O)C2CC2)c1C
Solvent: ClCCl
Product: CNc1c(S(C)(=O)=O)ccc(C(=O)C(=CN(C)C)C(=O)C2CC2)c1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 1.58 g (5.1 mmol) of 1-cyclopropyl-3-(3-methylamino-2-methyl-4-methylsulfonylphenyl)propane-1,3-dione and 2.0 ml (15.3 mmol) of N,N-dimethyl formamide dimethyl acetal was stirred for 3 h at RT. The mixture was treated with 10 ml of CH2Cl2, stirred for 2 h at an oil-bath temperature of 50° C., left to stand overnight, stirred for 1 d at an oil-bath temperature of 50° C., and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel. This gave 0.85 g of product in 93% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=1.ClC1C=CC=CC=1C1C(C2C=CC(Cl)=CC=2)=CC2N([C:36](=[O:39])NN=2)N=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]2[N:12]([C:36](=[O:39])[NH:15][N:14]=2)[CH:13]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Product: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cn12
Yield: 88 %

Procedure:
The title compound (190 mg, 88% yield) as a yellow foam was prepared from 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (200 mg, 0.61 mmol) in a manner analogous to that in which 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (Example 1G) was prepared. HPLC/MS: retention time=3.83 min, [M+H]+=356.1.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[CH3:14][O-:15].[Na+]>C(Cl)Cl>[CH3:14][O:15][CH2:3][CH:2]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[OH:1]
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCC(O)C1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
8-(oxiran-2-yl)-1,4-dioxaspiro[4.5]decane (202 mg, 1.10 mmol), prepared in the previous step, in DCM (20 mL) was dissolved in sodium methoxide solution (10 mL, 5 mmol, 0.5 M). The mixture was stirred, heating to reflux under argon overnight and then cooled to ambient temperature and concentrated in vacuo. After addition of saturated ammonium chloride solution and extraction with ethyl acetate, the organic layers were concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0-50% ether) to afford the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH3:2].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1C=C>ClCCl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[F:15])[CH3:2]
Reactant: C=Cc1ccccc1F
Reactant: C=CCCCCCCCC(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCC=Cc1ccccc1F
Temperature: 40 °C
Yield: 56.8 %

Procedure:
To a solution of 9-decenoic acid ethyl ester (Tetrahedron 2003, 59, 7973; 500 mg, 2.53 mmol) and 2-fluorostyrene (617 mg, 5.05 mmol) in dichloromethane (12.5 mL) was added dichloro(1,3-dimesityl-4,5-dihydroimidazol-2-ylidene)(phenylmethylene)(tri-cyclohexylphosphine)ruthenium (107 mg, 0.13 mmol). The mixture was flushed with nitrogen and sealed in a pressure tube, then heated at 40° C. for 18 h. After cooling and evaporation of the solvent, the product was purified by chromatography (SiO2, heptane-dichloromethane 3:1) to afford 10-(2-fluoro-phenyl)-dec-9-enoic acid ethyl ester (420 mg, 57%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([NH:24][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10022.7 %

Procedure:
To a solution of benzenesulfonyl chloride (722 μL, 0.00566 mol), potassium carbonate (0.939 g, 0.00679 mol) in acetonitrile (15 mL, 0.29 mol) was added tert-butylamine (0.652 mL, 0.00623 mol). The resulting mixture was stirred at r.t. for 30 minutes, followed by filtration and concentration. The resulting residue was diluted with ethyl acetate, and the resulting solution was washed with water then with brine, then dried with MgSO4 followed by concentration. The crude material was purified by flash chromatography on silica gel with 40% AcOEt in hexanes to give the desired compound (121 g, 85% yield). MS (ESI): 236.0 (M+Na+).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][CH:23]([F:25])[F:24])=[CH:14][C:13]=2Cl)=[CH:6][CH:5]=1.[F:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][CH:23]([F:25])[F:24])=[CH:14][C:13]=2[N:33]2[CH2:34][CH2:35][C@@H:31]([F:30])[CH2:32]2)=[CH:6][CH:5]=1
Reactant: F[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(NCC(F)F)cc1N1CC[C@@H](F)C1

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(4-trifluoromethoxy-phenyl)-2-chloro-4-(2,2-difluoro-ethylamino)-5-nitro-benzoic acid amide (177 mg, 0.40 mmol), (R)-3-fluoro-pyrrolidine×HCl (56 mg, 0.44 mmol), DIPEA (0.55 mL, 3.2 mmol) and MeCN (5 mL).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+]>CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]nnc4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of methyl 2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140 mg, 0.37 mmol) in methanol (25 mL) and water (5 mL) was added sodium hydroxide (45 mg, 1.11 mmol) with stirring for overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL), and adjusted to pH 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (110 mg, 82%).
Reaction SMILES: [CH2:1](C([SnH3])=C(CCCC)CCCC)[CH2:2]CC.[Cl:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][NH:22][C:23]([C:25]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[C:31](I)[CH:32]=3)[N:27]([CH3:37])[CH:26]=2)=[O:24])=[CH:19][CH:18]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][NH:22][C:23]([C:25]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH:1]=[CH2:2])[CH:32]=3)[N:27]([CH3:37])[CH:26]=2)=[O:24])=[CH:19][CH:18]=1
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Product: C=Cc1ccc2c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Tributylvinylstannane (0.32 mL) is added to a solution of N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.45 g) from Preparation No. 39 and PdCl2(PPh3)2 (70 mg). The mixture is stirred at room temperature for 1 h and then is heated to 60° C. for 30 min. After cooling to room temperature, the reaction mixture is poured into water (60 mL), filtered, and washed with water (20 mL) and diethyl ether (20 mL). The crude product is purified by recrystallization from acetonitrile to afford 0.20 g (57%) of the title compound as a white solid.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](Cl)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]>>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([N:8]2[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: CN1CCNC(CN2CCCC2)C1
Agent: Cl
Product: CN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCCC2)C1
Yield: 127.3 %

Procedure:
The procedure described in Example 17. but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of tciethylamine and 0.8 g of 3,4-dichlorophenylacetyl chloride, to afford 1.01 g of the title compound, melting at 223°-227° C. (dec.).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:5].[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:25])[CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[O:5])(=[O:41])=[O:42])[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: NCC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(CNS(=O)(=O)c1ccc(Cl)c(Cl)c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-amino-N-{l-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide hydrochloride salt was reacted with 3,4-dichlorophenylsulphonyl chloride to give 2-(3,4-dichlorophenylsulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide as a gum (0.17 g, 27%);
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][CH2:8][CH:9]1[CH2:13][CH:12]([OH:14])[C:11](=[O:15])[NH:10]1)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O>[OH:14][CH:12]1[C:11](=[O:15])[NH:10][CH:9]([CH2:8][CH2:7][C:6]([OH:16])=[O:5])[CH2:13]1
Reactant: CC(C)(C)OC(=O)CCC1CC(O)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(O)CCC1CC(O)C(=O)N1

Procedure:
4-Hydroxy-5-oxo-2-pyrrolidinepropanoic acid t-butyl ester (1.87 g) and trifluoracetic acid (1.2 g) in 10 ml of N,N-dimethylformamide was heated at 100° C. until disappearance of starting material by thin layer chromatography. After concentration under reduced pressure, the resulting solid is washed with acetone and filtered to give 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid with mp 129°-132° C. NMR (DMSOD6) and 12.14 (s, 1H), 7.96 (d, J=5 Hz, 1H), 5.37 (m, 1H), 4.00 (m, 1H), 2.60-1.09 (m, 6H). IR (cm-1) 3420, 3080, 2030, 2920, 1698, 1494, 1387, 1284.
Reaction SMILES: [CH3:1][SH:2].O[CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1>FC(F)(F)C(O)=O>[CH3:1][S:2][CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1
Reactant: CS
Reactant: O=c1[nH]cc(CO)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CSCc1c[nH]c(=O)[nH]c1=O
Reaction time: 2 h

Procedure:
Methylmercaptan is introduced into a solution of 14 g of 5-hydroxymethyluracil in 80 ml of trifluoroacetic acid over the course of one hour until saturation is reached, the temperature being kept at 25° C. The solution is then left to stand for 2 hours, the solvent is evaporated under reduced pressure and the residue is crystallised from glacial acetic acid. 5-Methylthiomethyluracil is obtained as colourless crystals of melting point 239°-241° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=1[NH2:6])[CH2:2][CH3:3].Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:4]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=1[NH:6][CH2:13][CH:14]=[O:15])[CH2:2][CH3:3]
Reactant: O=CCCl
Reactant: CCCc1ccc(F)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCc1ccc(F)cc1NCC=O
Temperature: 150 °C

Procedure:
2-Propyl-5-fluoroaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-propyl-5-fluoroanilino)acetaldehyde.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[N:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1)[NH2:37]>CN(C=O)C.O>[N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]2[O:11][N:37]=[C:36]([C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:42][CH:43]=3)[N:35]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of 5-nitro-1H-pyrazole-3-carboxylic acid (1.0 g, 6.24 mmol) in dry DMF (50 mL) was added EDCl (1.20 g, 6.24 mmol), HOBT (0.84 g, 6.24 mmol) and N′-hydroxy-4-(trifluoromethoxy)benzenecarboximidamide (1.37 g, 6.24 mmol). The mixture was stirred at rt for 2 h, and then warmed to 140° C. and stirred for additional 2 h. After being cooled to rt, the mixture was diluted with water (100 mL) and extracted with ethyl acetate. The organic extract was successively washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was removed in vacuo, and the residue was redissolved in warm acetonitrile (3 mL) to which tert-butyl methyl ether (2 mL) was added. The title compound precipitated and was obtained as a white solid after filtration, washing with tert-butyl methyl ether and drying in vacuo (1.2 g, 56%): 1H NMR (500 MHz, DMSO-d6) δ 8.20 (d, 2H), 7.58 (d, 2H), 7.34 (s, 1H); ES-MS m/z 340 (M-H)−; HPLC RT (Method J) 4.87 min.