Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18]CC2C=CC=CC=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6]>C(O)C>[F:1][CH:2]([F:26])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)COC(F)F)c1
Solvent: CCO
Product: COC(=O)c1cc(O)cc(O[C@@H](C)COC(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 352 %

Procedure:
Methyl 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-[(phenylmethyl)oxy]benzoate (0.48 g, 1.08 mmol) was dissolved in ethanol (10 mL) and THF (10 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (140 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at RT for 20 hours until completion. The reaction mixture was evacuated and purged with argon (3 times) then the catalyst removed by filtration through Celite®. The filtrate was concentrated in vacuo to give the desired compound as a colourless oil (1.05 g). 1H NMR δ (CDCl3): 1.35 (d, 3H), 3.90 (s, 3H), 3.90-4.02 (m, 2H), 4.57-4.64 (m, 1H), 5.20 (s, 1H), 6.26 (t, 1H), 6.63 (t, 1H), 7.14-7.15 (m, 1H), 7.17-7.18 (m, 1H); m/z 275 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH3:17])[NH:10][CH3:11].[Br:18]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:18])=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH3:17])[NH:10][CH3:11]
Reactant: CNC(Cc1ccccc1N)c1ccsc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CNC(Cc1cc(Br)ccc1N)c1ccsc1C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
A stirred solution of 3.0 g of 2-amino-N-methyl-α-(2-methyl-3-thienyl)benzeneethanamine in 50 ml of N,N-dimethylformamide was treated with a solution of 2.6 g of N-bromosuccinimide in 50 ml of N,N-dimethylformamide and allowed to stand overnight at room temperature. Evaporation of the volatiles afforded an oil which was purified by HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol). The resultant oil was dissolved in diethyl ether, filtered and concentrated. Trituration with diethyl ether afforded 1.2 g of 2-amino-5-bromo-N-methyl-α-(2-methyl-3-thienyl)benzeneethanamine, mp 72.5°-74° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([OH:11])=O)[C:6](=[O:12])[C:5]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.Br.Br.[S:24]1[C:28]2[CH2:29][CH:30]([NH2:33])[CH2:31][CH2:32][C:27]=2[N:26]=[C:25]1[NH2:34]>>[NH2:34][C:25]1[S:24][C:28]2[CH2:29][CH:30]([NH:33][C:9](=[O:11])[CH2:8][N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([NH:13][CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:6]3=[O:12])[CH2:31][CH2:32][C:27]=2[N:26]=1
Reactant: Nc1nc2c(s1)CC(N)CC2
Reactant: Cc1ccc(NCCc2ccccc2)c(=O)n1CC(=O)O
Agent: Br
Product: Cc1ccc(NCCc2ccccc2)c(=O)n1CC(=O)NC1CCc2nc(N)sc2C1

Procedure:
The title compound was prepared from 2-[6-methyl-2-oxo-3 -(phenethylamino)-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a yellow crystalline solid compound.
Reaction SMILES: CCN(CC)CC.Cl.[S:9]1[C:13]([NH2:14])=[CH:12][N:11]=[CH:10]1.[CH3:15][C:16](OC(C)=O)=[O:17]>C(Cl)Cl>[S:9]1[C:13]([NH:14][C:16](=[O:17])[CH3:15])=[CH:12][N:11]=[CH:10]1
Reactant: Nc1cncs1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cncs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
To a solution of Et3N (0.31 mL, 2.20 mmol) and thiazol-5-amine hydrochloride (0.2 g, 1.46 mmol) from example 1.2 in DCM (10 mL) was added Ac2O (0.21 mL, 2.20 mmol). The mixture was stirred at room temperature for 3 h and then concentrated. The resulting mixture was deposited onto silica gel and loaded onto a silica gel column and eluted with EA to give the title compound (0.14 g, 0.98 mmol, 70%).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C([O:18][CH:19](O)[CH:20]([F:22])[F:21])C>>[F:21][CH:20]([F:22])[CH:19]([C:3]1[N:4]([CH3:9])[CH:5]=[CH:6][C:7](=[O:8])[C:2]=1[OH:1])[OH:18]
Reactant: Cn1ccc(=O)c(O)c1
Reactant: CCOC(O)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc(=O)c(O)c1C(O)C(F)F
Temperature: 50 °C
Yield: 25 %

Procedure:
A sealed suspension of 3-hydroxy-1-methypyridin-4(1H)-one (1.00 g, 8.0 mmol) and potassium carbonate (0.11 g, 0.8 mmol) in 2.4 mL of difluoroacetaldehyde ethyl hemiacetal was heated to 50° C. for 18 h. The volatile components were evaporated under reduced pressure. The residue was dissolved in 3 mL of de-ionized water then cooled in an ice-water bath, and the pH was adjusted to 5-6 with a 1N HCl solution. The precipitate was collected by suction filtration and dried. Thus, the title compound Apo7078 was obtained (410 mg) as a white solid. Yield=25%; 1H NMR (400 MHz, CD3OD) δ (ppm): 7.62 (d, J=7.1 Hz, 1H), 6.41 (d, J=7.1 Hz, 1H), 6.30 (dt, 3J=55.8 Hz, 2J=5.1 Hz, 1H), 5.45 (dt, 2J=5.1 Hz, 3J=11.4 Hz, 1H), 3.96 (s, 3H); MS m/z 206 [M+1], 188 (100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: OCCCCCCCCCCCBr
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCBr)cc1

Procedure:
A solution of 30 g. 11-bromoundecyl alcohol and 25.0 g. 4-toluenesulfonyl chloride in 250 ml. dry ether is cooled with stirring in an ice-water bath. To this is added dropwise 13.2 g. triethylamine in 50 ml. ether. After addition, the solution is stirred in the cold for 1 hour and filtered. The ether is washed with 100 ml. 10% hydrochloric acid solution, 100 ml. brine, dried and evaporated to yield the title compound as an oily solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[CH2:12](Br)[C:13]#[CH:14].O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][O:10][C:12]#[C:13][CH3:14])[CH2:6][O:5]1
Reactant: C#CCBr
Reactant: CC1(C)OCC(CO)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CC#COCC1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (1.32 g, 55 mmol) was added to a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (Aldrich) in THF (60 mL), and the resulting mixture was heated at reflux for 90 min then cooled to 0° C. Tetrabutylammonium iodide (370 mg), and propargyl bromide (80% in toluene, 6.22 mL, 50 mmol) (Aldrich) were added successively. After stirring for 150 min. at room temperature, 20 mL water was added and the THF was evaporated in vacuo. The aqueous layer was then extracted with diethyl ether (4×50 mL), and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to yield rac-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxyl-1-propyne.
Reaction SMILES: CS(O)(=O)=O.CCOC(C)=O.C(OC([N:19]1[C@H:23]([C:24](=[O:29])[NH:25][CH2:26][CH:27]=[CH2:28])[C:22]([CH3:31])([CH3:30])[S:21][CH2:20]1)=O)(C)(C)C>O>[CH2:26]([NH:25][C:24]([C@@H:23]1[C:22]([CH3:31])([CH3:30])[S:21][CH2:20][NH:19]1)=[O:29])[CH:27]=[CH2:28]
Reactant: C=CCNC(=O)[C@H]1N(C(=O)OC(C)(C)C)CSC1(C)C
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCNC(=O)[C@H]1NCSC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonic acid (155 mL; 2.39 mol) was added dropwise to the EtOAc solution of (4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester in a 3-L flask. After stirring at room temperature overnight, the solution was cooled to 7° C. and H2O (400 mL) was poured in. The mixture was transferred to a 4-L separatory funnel [using H2O (30 mL) for rinsing] and the layers were separated. The organic fraction was extracted with H2O (190 mL). The combined H2O extracts were transferred to a 5-L flask and were cooled to 8° C. The pH was adjusted from 0.4 to 9.3 using 3 N NaOH (˜1.05 L). 2-Methyltetrahydrofuran (1.55 L) was poured in, followed by the addition of NaCl (150 g). The ice bath was removed and the mixture was allowed to warm to room temperature. The pH was readjusted to 9.0 using 3 N NaOH (˜1 mL). The mixture was transferred to a 4-L separatory funnel, using 2-methyltetrahydrofuran (50 mL) for rinsing, and the layers were separated. The aqueous phase was extracted with 2-methyltetrahydrofuran (950 mL). The organic extracts were vacuum-filtered through Celite directly into a 5-L distillation flask, using 2-methyltetrahydrofuran (200 mL) for rinsing. The solution was dried azeotropically and concentrated to a volume of 1.2 L by distillation of 2-methyltetrahydrofuran at one atmosphere. A measured aliquot was concentrated and weighed, which showed that 161 g of (4R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide was present in solution [84% from (4R)-5,5-dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester]. This solution was then carried on directly into the next step. The concentrated aliquot from above yielded (4R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide as a crystalline solid: mp=45–47° C., 1H NMR (300 MHz, CDCl3) δ 6.73 (br s, 1H), 5.87 (app ddt, J=10.2, 17.1, 5.7 Hz, 1H), 5.17–5.27 (m, 2H), 4.27 (AB q, JAB=9.7 Hz, Δν=22.5 Hz, 2H), 2.94 (app tt, J=1.5, 5.8 Hz, 2H), 3.51 (s, 1H), 1.74 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, DCl3) δ 169.7, 134.4, 116.9, 74.8, 57.2, 51.6, 41.9, 29.1, 27.3; MS (CI) m/z 201.1063 (201.1062 calcd for C9H17N2OS, M+H+); elemental analysis calcd for C9H16N2OS: C, 53.97; H, 8.05; N, 13.99; found: C, 53.93; H, 8.09; N, 14.07.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([NH:10][CH2:11][C:12]1([C:18]2[S:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:9])[NH2:4].Cl[C:33](=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>N1C=CC=CC=1>[C:23]1([C:21]2[N:22]=[C:18]([C:12]3([CH2:11][NH:10][C:8]([C:7]4[CH:6]=[C:5]([C:3]5[N:4]=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[O:1][N:2]=5)[CH:31]=[CH:30][CH:29]=4)=[O:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:19][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=NO)c1cccc(C(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2cccc(C(=O)NCC3(c4nc(-c5ccccc5)cs4)CCOCC3)c2)no1
Temperature: 0 °C
Yield: 84.2 %

Procedure:
3-(N′-Hydroxycarbamimidoyl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide (6.8 g, 15.57 mmol) was dissolved in anhydrous pyridine (68 mL) and the reaction mixture was cooled to 0° C. Ethyl chlorooxoacetate (5.2 mL, 46.73 mmol) was added dropwise, and the reaction mixture was heated at 60° C. for 1 h, quenched with 1.5N HCl solution, and diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 25-30% EtOAc in petroleum ether) to afford ethyl 3-(3-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (6.8 g, yield 87%). 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=7.9 Hz, 1H), 8.11-8.09 (m, 1H), 7.78-7.76 (m, 1H), 7.61-7.59 (m, 2H), 7.44 (s, 1H), 7.32-7.27 (m, 1H), 7.23-7.21 (m, 3H), 4.62-4.57 (q, J=7.0 Hz, 2H), 3.97-3.94 (m, 2H), 3.81-3.76 (m, 2H), 3.56-3.50 (m, 2H), 2.41-2.37 (m, 2H), 2.19-2.12 (m, 2H), 1.53-1.50 (t, J=7.2 Hz, 3H). MS (ESI) m/z: Calculated for C27H26N4O5S: 518.16. found: 517.1 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:15])=[C:9]([CH2:12][CH:13]=[CH2:14])[CH:10]=2)[CH2:5][C:4]1=[O:16])[CH3:2].B.O1CCCC1.[OH-].[Na+].OO>O1CCCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[CH2:5][C:4]1=[O:16])[CH3:2]
Reactant: C=CCc1cc2c(cc1O)CC(=O)N2CC
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(=O)Cc2cc3c(cc21)C=CCO3
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 3.0 g. (13.8 mmoles) of 1-ethyl-5-hydroxy-6-allyloxindole (Preparation W2) in 30 ml. of tetrahydrofuran at 0° C. was slowly added 13.8 ml. (13.8 mmoles) of a 1M borane-tetrahydrofuran solution. The reaction was stirred for 30 minutes followed by the addition of 50 ml. of 1N sodium hydroxide solution and 25 ml. of a 30% hydrogen peroxide solution. After stirring the reaction for 5 minutes it was acidified with 25 ml. of 4N hydrochloric acid and extracted with methylene chloride (10×50 ml.). The extracts were combined, dried and concentrated to give the crude product, which was purified by chromatographing on 120 g. of silica gel using 5% methanol-methylene chloride as the eluent to give 1.85 g. (56% yield) of the desired product.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[N:13][C:14]=1Cl>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[N:13][C:14]=1[O:7][CH2:6][CH:3]1[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(Cl)c(Cl)n1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(Cl)c(OCC2CC2)n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
Sodium hydride (CAN 7646-69-7, 60% w/w, 1.05 g, 26 mmol) was added to cyclopropylmethanol (CAN 2516-33-8, 7.5 g) at 0° C. and the mixture was stirred for 1 h. 5,6-Dichloro-pyridine-2-carboxylic acid (1 g, 5 mmol) was added and the mixture was heated to 95° C. for 3 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and adjusted to pH=3.0 by hydrochloric acid (3 N). The solution was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (3×30 mL) and brine (2×40 mL) and evaporated to dryness to give the crude product (0.35 g, 25%), which was used in the next step without further purification, MS (EI): m/e=228.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](OC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].BrC[C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:26]([O:28][CH3:29])=[O:27])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)Nc1ccn(-c2ccc(OC)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Temperature: 85 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-amino-1H-pyrazole-5-[(2′-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide (1.0 g, 1.92 mmol) in 10 mL of DMF was added sodium bicarbonate (0.24 g, 2.88 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol) The resulting mixture was stirred at 85° C. for 16 h. The reaction was not complete so additional portions of sodium bicarbonate (0.48 g, 5.76 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol) were added and the reaction was stirred at 95° C. for 6 h longer. The reaction was cooled to ambient temperature and was diluted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 5 mL of trifluoroacetic acid and was stirred at reflux for 20 min and then was cooled to ambient temperature and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 450 mg (44%) of the title compound as a white powder. LRMS (ES+): 536.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[N:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=O)[O:5][CH3:6].[CH3:16][O:17][N:18]=[C:19]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:20](=[N:22][NH2:23])[CH3:21]>CO>[CH3:1][O:2][C:3](=[O:15])[N:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[N:23][N:22]=[C:20]([CH3:21])[C:19](=[N:18][O:17][CH3:16])[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[O:5][CH3:6]
Reactant: COC(=O)N(OC)c1ccccc1C=O
Reactant: CON=C(C(C)=NN)c1ccc(F)cc1
Solvent: CO
Product: CON=C(C(C)=NN=Cc1ccccc1N(OC)C(=O)OC)c1ccc(F)cc1
Yield: 23.9 %

Procedure:
A solution of 1.05 g of (2-formyl-phenyl)-N-methoxycarbamic acid methyl ester and 1.05 g of 1-(4-fluorophenyl)-2-hydrazono-propan-1-on-O-methyl-oxime in 5 ml of methanol is stirred at room temperature for 4 hours. The resulting by-product (symmetric azine of 1-(4-fluorophenyl)-2-hydrazono-propan-1-on-O-methyl-oxime) is removed by filtration and the filtrate is placed in a refrigerator over night. The product which has crystallised is filtered off (1.0 g). By concentrating the mother liquor and by means of fractional crystallisation of the residue, a further 0.48 g of the title compound are obtained in the form of yellow crystals having a melting point of 88-90° C.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][NH:32][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: O=c1c(NCCC2CCN(Cc3ccccc3)CC2)c(Nc2cccnc2)c1=O
Temperature: 150 °C

Procedure:
3-Ethoxy-4-(pyridine-3-yl-amino)-3-cyclobutene-1,2-dione (164 mg, 0.75 mmol) prepared according to example 1A and 2-(1-benzylpiperidin-4-yl)-ethylamine (196 mg, 0.90 mmol) in EtOH (4 mL) were stirred and heated to 150° C. in a sealed vessel in a microwave synthesizer for 3 min. After cooling to r.t. the precipitate was filtered off and washed with EtOH (3×3 mL) and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=2)[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Reactant: Fc1cccc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3-fluorobenzyl chloride gave the title compound. ES-MS m/e (%): 567.3(M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])[CH:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].Cl.[OH:31][C:32]1([CH3:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([N:35]4[CH2:36][CH2:37][C:32]([OH:31])([CH3:38])[CH2:33][CH2:34]4)=[O:28])=[O:24])[CH:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCC(=O)O)c3)ccc21
Reactant: CC1(O)CCNCC1
Agent: Cl
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCC(=O)N4CCC(C)(O)CC4)c3)ccc21
Yield: 21.9 %

Procedure:
The reaction similar to Example 5 was performed by using ((4-(1-ethylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)acetic acid (149 mg, 0.37 mmol) and 4-hydroxy-4-methylpiperidine monohydrochloride (68 mg, 0.45 mmol, Production example 8-3); purification was performed by silica gel column chromatography (Fuji Silysia BW-300, eluent, ethyl acetate:methanol=9:1; Fuji Silysia NH, eluent, ethyl acetate:methanol=10:1; and again Fuji Silysia BW-300, eluent, ethyl acetate-methanol system); and the obtained crystals were suspended in diethyl ether and filtered off, washed with diethyl ether and dried under aeration to yield the title compound as colorless crystals (40 mg, 0.081 mmol, 22%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.2 %

Procedure:
A solution of 3.5 g (9.83 mmol) of 1,1-dimethylethyl 4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate, prepared in Step 4.1, in 20 ml of dichloromethane is admixed with 10 ml of trifluoroacetic acid and the solution is stirred at ambient temperature for 1 hour. It is evaporated to dryness and then the residue is taken up in 30 ml of toluene, which is evaporated again to dryness. The residue is subsequently washed with pentane and then taken up in a mixture of 60 ml of dichloromethane and 20 ml of 4N aqueous ammonia solution. It is stirred vigorously for 15 minutes and then the organic phase is decanted, dried over sodium sulfate and evaporated to dryness, to give 2.7 g of product in oil form, which is used as it is in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH:9]=[C:10]([Cl:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:17][CH:18]1[CH2:24][C:23](=[O:25])[O:22][C:20](=[O:21])[CH2:19]1>ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:25])[CH2:24][CH:18]([CH3:17])[CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:3]=1[CH:9]=[C:10]([Cl:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CCOC(=O)C(Cl)=Cc1cc(N)ccc1Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cl)=Cc1cc(NC(=O)CC(C)CC(=O)O)ccc1Cl
Reaction time: 3 h

Procedure:
5.2 g of 4-chloro-3-(2-chloro-2-ethoxycarbonyl-ethenyl)aniline in 30 ml of dichloromethane were added dropwise at 25° C. to a solution of 2.56 g of 3-methylglutaric anhydride in 50 ml of dichloromethane. After 3 h, the deposited precipitate was removed and washed with dichloromethane. Yield: 5 g; m.p.: 137°-138° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH2:35])[CH2:23][CH3:24])[CH3:21]>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH:35][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: CCN(CC)CC1CCCCN1CCCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 47 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[2-[(diethylamino)methyl]-piperidin-1-yl]propanamine in a yield of 47% of theory. Colourless crystals, m.p. 160°-161° C. (acetonitrile).