Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]1=[O:10].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][N:2]1[CH:7]=[C:6]([CH:8]([OH:9])[C:12]([F:14])([F:13])[F:11])[CH:5]=[CH:4][C:3]1=[O:10]
Reactant: Cn1cc(C=O)ccc1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1cc(C(O)C(F)(F)F)ccc1=O
Yield: 45.9 %

Procedure:
According to Reference Example 8-12, by use of 1-methyl-5-formyl-2-(1H)-pyridone (309 mg, 2.25 mmol), (trifluoromethyl)trimethylsilane (666 μL, 45.1 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 225 μL, 0.225 mmol) and tetrahydrofuran (10.0 mL), the mixture was stirred and reacted at room temperature fort hour. Then, purification by column chromatography (ethyl acetate) was performed to give 1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-2(1H)-pyridone (Compound ET) (214 mg, yield: 46%).
Reaction SMILES: [K].[CH3:2][CH:3]([CH3:5])[O-:4].[K+].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1>CC(O)C.[Cu]>[CH:3]([O:4][C:12]1[CH:13]=[C:8]([Br:7])[CH:9]=[N:10][CH:11]=1)([CH3:5])[CH3:2]
Reactant: CC(C)[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Cu]
Agent: [K+]
Agent: [K]
Solvent: CC(C)O
Product: CC(C)Oc1cncc(Br)c1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Potassium metal (6.59 g, 168.84 mmol) was dissolved in dry 2-propanol (60.0 mL) under nitrogen. The resulting potassium isopropoxide was heated with 3,5-dibromopyridine (20.00 g, 84.42 mmol) and copper powder (1 g, 5% by weight of 3,5-dibromopyridine) at 140° C. in a sealed glass tube for 14 h. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether (4×200 mL). The combined ether extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product obtained was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-hexane (1:9, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing a pale-yellow oil (12.99 g, 71.2%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)[CH2:24][C:25]([N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)=[O:26])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CNC2CC2)cc1OC
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: COc1ccc(CN(C(=O)CN(c2cccc(N(C)C)c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc1OC

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with cyclopropyl-(3,4-dimethoxy-benzyl)-amine
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([Br:26])[CH:14]=1)[C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])C.O.[NH2:30][NH2:31]>C(O)(=O)C>[Br:26][C:15]1[CH:14]=[C:13]([C:6]2[CH:5]=[C:4]([OH:3])[N:30]=[N:31][C:7]=2[CH2:8][CH2:9][CH2:10][CH3:11])[CH:18]=[CH:17][C:16]=1[O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCCCC(=O)C(c1ccc(OC2CCCCC2)c(Br)c1)C(O)C(=O)OCC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nnc(O)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(3-bromo-4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester (4.39 mmol, 2.0 g) and hydrazine hydrate (2.0 mL) in acetic acid (10 mL) was kept stirring at 120° C. for 3 h. The reaction mixture was concentrated under reduced pressure and to the residue was added water, extracted with ethyl acetate dried and concentrated under reduced pressure, dried to provide 5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-ol (1.7 g).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=[O:18])([O-])[O-:16].[K+].[K+]>C(O)C>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]2[CH2:13][CH2:8][CH:9]2[C:15]([O:16][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(OCc1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Yield: 52 %

Procedure:
An alternative to the procedures of Examples 1b-1c, (R)-1-t-butyloxycarbonyl-2-azetidinemethanol was prepared from γ-butyrolactone according to the procedure of Rodebaugh, R. M. and Cromwell, N. H., (J. Heterocyclic Chem., 1969, 435). In this literature procedure, γ-butyrolactone was treated with bromine and catalytic phosphorus tribromide, then subsequently with benzyl alcohol and gaseous hydrogen chloride to afford benzyl α,γ-dibromobutyrate in 62% yield. This dibromide in ethanol was treated with one equivalent of benzhydrylamine and potassium carbonate at reflux for about 16 hours to afford benzyl N-diphenylmethylazetidine-2-carboxylate in 52% yield. Hydrogenolysis in MeOH over Pd(OH)2 afforded racemic azetidine-2-carboxylic acid in 62% yield. Following the procedure of Rodebaugh, R. M. and Cromwell, N. H., (J. Heterocyclic Chem., 1969, 993), racemic azetidine-2-carboxylic acid was converted to the N-Cbz derivative by treatment with benzyl chloroformate in aqueous NaOH at 0-5° C. Following isolation in quantitative yield, the Cbz derivative in methanol was treated with one equivalent of L-tyrosine hydrazide to precipitate the tyrosine hydrazide salt of (R)-azetidine-2-carboxylic acid in 77-87% yield. (R)-1-Cbz-azetidine-2-carboxylic acid was liberated from the salt by normal extractive procedures. Hydrogenolysis of the free acid by treatment of a methanol solution with hydrogen gas at 4 atm in the presence of 10% Pd/C for 19 h afforded (R)-azetidine-2-carboxylic acid, which was isolated in 88% yield by trituration with methanol. This product was treated with di-tert -butyl dicarbonate and N-methylmorpholine in dioxane/H2O (1:1) to afford (R)-1-Boc-azetidine-2-carboxylic acid in quantitative yield. Treatment of a THF solution of (R)-1-Boc-azetidine-2-carboxylic acid with borane-methyl sulfide complex for 16 h at ambient temperature afforded the title compound in 92% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)([N:16]=[C:17]=S)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:30]1([NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36].CCN=C=NCCCN(C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:16][C:17]2[NH:37][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]=2)([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Nc1ccccc1N
Reactant: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(N=C=S)c2ccc(Cl)cn2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CC(Cl)Cl
Product: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(Nc2nc3ccccc3[nH]2)c2ccc(Cl)cn2)c1
Temperature: 80 °C
Yield: 47.2 %

Procedure:
5-chloro-2-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-isothiocyanato-2-phenylethyl)pyridine (0.036 g, 0.083 mmol) in dichloroethane (1 mL) in a two drum vial was added phenylenediamine (12 mg, 0.108 mmol) and TEA (13 mL, 0.091 mmol). The reaction was heated at 80° C. for 2 hours. EDCI (24 mg, 0.124 mmol) was added and the reaction was continued to be heated at 80° C. overnight. The reaction was concentrated and the crude mixture was purified by ISCO chromatography (12 g column) using hexanes/EtOAc (0-40% over 25 min) to give N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-1H-benzo[d]imidazol-2-amine as a white solid (20 mg, 47% yield). LCMS: 3.2 min [M+1] 511.22 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CD3OD) d ppm 4.01-4.10 (m, 1H), 4.51 (d, J=13.21 Hz, 1H), 6.48 (d, J=7.34 Hz, 2H), 6.93-7.04 (m, 5H), 7.22 (dd, J=5.50, 3.06 Hz, 2H), 7.34 (d, J=8.31 Hz, 1H), 7.51-7.58 (m, 1H), 7.71-7.77 (m, 2H), 7.82 (dd, J=8.56, 2.45 Hz, 1H), 8.41 (d, J=2.45 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([S:25][CH3:26])=[N:23][N:24]=2)[N:21]=1>>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([S:25][CH3:26])=[N:23][N:24]=3)[N:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nnc2ccc(Cl)nn12
Reactant: c1ccc(CN2CCCNCC2)cc1
Product: CSc1nnc2ccc(N3CCCN(Cc4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzyl-1,4-diazepane and 6-chloro-3-methylsulfanyl-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 2 to give 6-(4-benzyl-1,4-diazepan-1-yl)-3-methylsulfanyl-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:27])=[C:7]([CH:24]=[CH:25][CH:26]=1)[C:8]([NH:10][C@@H:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:12]([OH:16])[C:13](O)=[O:14])=[O:9])(=[O:3])[CH3:2].[CH2:28]([NH:31][C:32]([C@@H:34]1[C:38]([CH3:40])([CH3:39])[S:37][CH2:36][NH:35]1)=[O:33])[CH:29]=[CH2:30].O.C(N=C=NC(C)C)(C)C>CC1CCCO1>[CH2:28]([NH:31][C:32]([C@@H:34]1[C:38]([CH3:40])([CH3:39])[S:37][CH2:36][N:35]1[C:13](=[O:14])[C@@H:12]([OH:16])[C@@H:11]([NH:10][C:8]([C:7]1[C:6]([CH3:27])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:26]=[CH:25][CH:24]=1)=[O:9])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:33])[CH:29]=[CH2:30]
Reactant: CC(=O)Oc1cccc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)O)c1C
Reactant: C=CCNC(=O)[C@H]1NCSC1(C)C
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CC1CCCO1
Product: C=CCNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(OC(C)=O)c2C)CSC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(2S,3S)-3-(3-Acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyric acid (271 g; 731 mmol) was added to a 5-L flask containing a solution of (4R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide (161 g; 804 mmol) in 2-methyltetrahydrofuran (1.20 L total solution), while using 2-methyltetrahydrofuran (500 mL) for rinsing. HOBt.H2O (32.6 g; 241 mmol) was added, using 2-methyltetrahydrofuran (50 mL) for rinsing. The white suspension was allowed to stir at room temperature for 10 min. Diisopropylcarbodiimide (119 mL; 760 mmol) was added in three portions (40 mL+40 mL+39 mL) at 30 min intervals. One hour after the final DIC addition, Celite (100 g) was added and the suspension was allowed to stir at room temperature for 3 h. The mixture was vacuum-filtered, while 2-methyltetrahydrofuran (400 mL) was used to rinse over the solids and wash the resulting filter cake. The filtrate was transferred to 4-L separatory funnel, using 2-methyltetrahydrofuran (50 mL) for rinsing. The solution was washed with 1 N HCl (1.25 L), and then with an aqueous solution of NaHCO3 (27 g), NaCl (134 g) and H2O (1.25 L). The resulting organic phase was transferred to a 3-L distillation flask and the solution was then reduced to a volume of 1.12 L by distillation of 2-methyltetrahydrofuran at one atmosphere. The solution was then diluted with 2-methyltetrahydrofuran (230 mL) to bring the total volume to 1.35 L. After cooling the solution to 23° C., the solution of crude acetic acid 3-{(1 S,2S)-3-[(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl}-2-methyl-phenyl ester on directly into the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20](CC2C=CC(Cl)=CC=2)[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chlorobenzyl)pyrrolidine (6.3 g, 11.4 mmol), Pd(OH)2 (1.68 g), HCO2H (3.7 mL), and methanol (80 mL) was stirred at 50° C. overnight. After the mixture was cooled to room temperature, the Pd catalyst was filtered off through Celite and the filtrate was concentrated. Column chromatography (SiO2, AcOEt, AcOEt/MeOH=5/1-4/1) gave (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (4.42 g, 90%) as a white solid:
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13](O)=[O:14])=[CH:8][O:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[OH:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([Cl:19])=[O:14])=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1coc2c(O)c(O)ccc2c1=O
Product: O=C(Cl)c1coc2c(O)c(O)ccc2c1=O

Procedure:
A mixture of 7,8-dihydroxychromone-3-carboxylic acid (6.6 g, 30 mmol) and thionyl chloride (25 ml) was refluxed for one hour, and the thionyl chloride was removed. After the addition of benzene to the residue, the mixture was evaporated to dryness and the residue was triturated with n-hexane to give the desired compound (7.2 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Cl>>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: ClCc1ccccn1
Reactant: O=C1CCNCC1
Agent: Cl
Product: O=C1CCN(Cc2ccccn2)CC1

Procedure:
1-(2-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidone and 2-picolyl chloride hydrochloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:50])([F:49])[O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([O:40][C:39]([F:38])([F:49])[F:50])=[CH:42][CH:43]=2)[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Product: O=C1C(Cc2ccc(OC(F)(F)F)cc2)CCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 36-2, using 281 mg of 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1, and using 4-trifluoromethoxybenzyl bromide in place of iodoethane, 383 mg (yield: 100%) of the captioned compound was obtained as a diastereomer mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25]>CC#N>[CH2:21]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10]1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COc1cccc(C2CCCNC2)c1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCN1CCCC(c2cccc(OC)c2)C1

Procedure:
To a solution of 3-(3-methoxyphenyl)piperidine (3.92 g, 0.02 mol) in CH3CN (100 ml), solid K2CO3 (5 g) was added and then the mixture was refluxed. A solution of pentyliodide (4.5 g, 0.021 mol) in CH3CN (10 ml) was added dropwise under 30 min. and then the mixture was refluxed for an additional 30 min. The solid was filtered off from the cooled mixture, and the solvent evaporated giving an oil which was chromatographed on a silica gel column with methanol as eluant. Yield 1.3 g (25%) of pure N-pentyl-3-(3-methoxyphenyl)piperidine (NMR) as an oil.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-])=O.Cl.[NH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)C(C)C)(C)C>C(#N)C.[Zn]>[NH2:1][CH2:4][CH:5]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(CN)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 148.3 %

Procedure:
Trans-□-Nitrostyrene (4.04 g, 27.1 mmol) was added to a solution of ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol), and N,N-diisopropylethylamine (9.43 mL, 54.2 mmol) in acetonitrile (70 mL). After 15 min, anhydrous hydrochloric acid gas was bubbled into the solution until acidic. The mixture was concentrated, redissolved in ethanol (60 mL) and aqueous hydrochloric acid (12 M; 30 mL), and cooled to 0° C. Zinc dust (8.80 g, 134 mmol) was added in portions over 5 min. After 0.5 h, the mixture was concentrated to remove ethanol and saturated aqueous sodium carbonate was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give the title compound (9.5 g). MS 237 (M+1).
Reaction SMILES: [CH2:1]([CH2:7][C:8]([NH2:10])=[S:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(OCC)(=O)C>N1C=CC=CC=1>[C:11]([NH:10][C:8](=[S:9])[CH2:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=S)CCc1ccco1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC(=S)CCc1ccco1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
8.56 g (0.05 mol) of 2-furfurylthioacetamide, 5.61 g (0.055 mol) of acetic anhydride, and 6.11 g (0.05 mol) of N,N-dimethyl-aminopyridine were dissolved in 50 ml of pyridine. The mixture was stirred at 80° C. for 16 hours. The solvent was distilled away from the reaction mixture, and the residue thus obtained was added to ethyl acetate and washed successively with water, 1N hydrochloric acid, water three times, and brine. A resultant organic extract layer was dried, and the solvent was distilled away therefrom, so that N-acetyl-2-furfurylthioacetamide was obtained in a yield of 7.11 g (60%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:14]1([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NN1CCNCC1
Yield: 104.7 %

Procedure:
To a solution of N-(4-benzyloxycarbonyl-1-piperazinyl)-tert-butoxycarboxamide (28 g) in methanol (250 ml) was added 10% palladium on carbon (5 g), and the mixture was stirred at ambient temperature under 3 atm of hydrogen for 1 hour. Palladium on carbon was filtered off and the filtrate was concentrated to give N-(1-piperazinyl)-tert-butoxycarboxamide (17.6 g).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[N:4]([CH2:10][CH2:11][C:12](O)=[O:13])[C:3]1=[O:15].C(Cl)(=O)C([Cl:19])=O.C(Cl)Cl>CN(C)C=O>[CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[N:4]([CH2:10][CH2:11][C:12]([Cl:19])=[O:13])[C:3]1=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1C(=O)N(CCC(=O)O)C(C)(C)C1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C(=O)N(CCC(=O)Cl)C(C)(C)C1=O
Temperature: 24 °C
Reaction time: 0.92 h
Yield: 97.7 %

Procedure:
A mixture of 10.71 g (50 mmol) 3-(3,5,5-trimethyl-2,4-dioxo-imidazolidin-1yl)-propionic acid (synthetized according to example 15), 31.73 g oxalyl chloride, 25 ml methylenechloride and 0.5 ml dimethylformamide is stirred for 1 h and 55 minutes at 24° C., thereafter evaporated in a rotary evaporator at 70° C. in vacuo, stripped 3 times with about 50 ml of toluene, evaporated completely do dryness and dried at 70° C./10.1 mbar. 11.36 g (97.6% of theory) of crystalline 3-(3,5,5-trimethyl-2,4-dioxo-imidazolidin-1yl)-propionylchloride are obtained.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[S:44][C:22]3=[CH:23][CH:24]=[C:25]4[C:30]([N:29]=[C:28]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([N:38]6[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]6)[CH:33]=5)[N:27]=[CH:26]4)=[C:21]3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.CO>C(Cl)Cl>[N:14]1([C:17]([C:19]2[S:44][C:22]3=[CH:23][CH:24]=[C:25]4[C:30]([N:29]=[C:28]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([N:38]6[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]6)[CH:33]=5)[N:27]=[CH:26]4)=[C:21]3[CH:20]=2)=[O:18])[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)c2cc3c(ccc4cnc(Nc5cccc(N6CCCCC6)c5)nc43)s2)CC1
Agent: Br
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cc2c(ccc3cnc(Nc4cccc(N5CCCCC5)c4)nc32)s1)N1CCNCC1
Yield: 60 %

Procedure:
4-[2-(3-Piperidin-1-yl-phenylamino)-thieno[2,3-h]quinazoline-8-carbonyl]-piperazine-1-carboxylic acid benzyl ester (205 mg, 0.34 mmol) was dissolved in dry DCM (4 mL) and HBr (2 mL, 33 wt % solution in AcOH) added. The resultant mixture was stirred at room temperature for 0.5 hours and concentrated under reduced pressure. The yellow gum obtained was partitioned between Et2O and dilute HCl. The aqueous layer was extracted with Et2O (1×10 mL). The aqueous layer was then basified with saturated Na2CO3 and extracted with DCM (3×10 mL). The DCM organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The brown gum obtained was redissolved in DCM, silica (˜5 mL) added and concentrated under reduced pressure. The solid obtained was subjected to column chromatography (10% MeOH in DCM, ˜100 mL silica) to give a bright yellow solid. This solid was triturated with Et2O, filtered and washed with Et2O (3×5 mL) and pentane (3×5 mL) to give a yellow powder (96.4 mg, 60% yield). MS (ES+) 473, (ES−) 472. δH (CDCl3) 1.5-1.9 (6H, m), 2.9-3.1 (4H, m), 3.2-3.3 (4H, m), 3.8-3.9 (4H, m), 6.7 (1H m), 7.2-7.3 (3H, m), 7.4 (1H, s), 7.6-7.7 (3H, m), 8.2-8.3 (1H, s), 9.1 (1H, s)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.[O-:17][C:18]#[N:19].[K+]>C(O)(=O)C.O>[N:15]1[C:9]2[NH:8][C:7]3[CH:16]=[C:3]([CH2:2][NH:1][C:18]([NH2:19])=[O:17])[CH:4]=[CH:5][C:6]=3[S:11][C:10]=2[N:12]=[CH:13][CH:14]=1
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)NCc1ccc2c(c1)Nc1nccnc1S2
Reaction time: 2 h
Yield: 14 %

Procedure:
A solution of 420 mg of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in acetic acid (2 ml)/water (4 ml) was heated to 70° C. and potassium cyanate (1 g in total) was added thereto over 2 hours. Then the reaction mixture was brought back to room temperature and diluted with water. The solid thus precipitated was filtered, washed well with water and recrystallized from dimethyl sulfoxide/ethyl acetate to thereby give 70 mg of the title compound as yellow crystals.