Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.CCCCCCCCCCCC.I[C:38]1[CH:39]=[C:40]([CH3:45])[CH:41]=[C:42]([CH3:44])[CH:43]=1>[Cu]I.O1CCOCC1>[C:1]([NH:9][NH:10][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCCCCCCCCCCC
Product: Cc1cc(C)cc(NNC(=O)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 63.6 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (2.0 mg, 0.0105 mmol, 1.0 mol %), benzoic hydrazide (170 mg, 1.25 mmol), K2CO3 (290 mg, 2.10 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (13 μL, 0.108 mmol, 11 mol %), dodecane (235 μL), 5-iodo-m-xylene (150 μL, 1.04 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 2:1; 15 mL fractions). Fractions 9-13 provided 159 mg (64% yield) of the product as a pale tan solid. 1H NMR (300 MHz, CDCl3): δ 8.06 (br s, 1H), 7.87−7.82 (m, 2H), 7.60−7.44 (m, 3H), 6.58 (s, 1H), 6.54 (s, 2H), 6.32 (br s, 1H), 2.25 (s, 6H).
Reaction SMILES: CN(C)[CH:3]=[C:4]([N:9]=[CH:10]N(C)C)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][N:16]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17]1>C(O)(=O)C.C(O)(C(F)(F)F)=O>[CH3:15][N:16]1[C:20]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[N:9]=[CH:10][C:19]=2[C:18]([CH3:21])=[CH:17]1
Reactant: COC(=O)C(=CN(C)C)N=CN(C)C
Reactant: Cc1ccn(C)c1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(cn1)c(C)cn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
In a 500 ml round bottom flask, methyl 3-(dimethylamino)-2-((dimethylamino)methyleneamino)acrylate (1A, 12 g, 61 mmol) was dissolved in acetic acid (45 ml) and TFA (15 ml). 1,3-Dimethyl-1H-pyrrole (5.8 g, 61 mmol) was added and the mixture was stirred at room temperature for an hour and then at 110° C. for 4 hours. Volatiles were then evaporated from the reaction mixture, the residue was cooled in an ice bath and ice cold saturated K2CO3 solution (200 ml) was slowly added to it. The mixture was extracted with EtOAc (3×250 ml). Combined organic layers were then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified on a silica column using hexane-EtOAc (0-100%). Desired product methyl 1,3-dimethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1J, 6.8 g, 55%) was obtained.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([CH2:19][CH3:20])[C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH2:21][CH3:22])[CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[C:17]([CH2:19][CH3:20])=[CH:18][C:2]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:3][C:4]=2[CH2:21][CH3:22])=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: CCc1cc(Br)cc(CC)c1C(=O)NCc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1cc(N2CCOCC2)cc(CC)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 120 °C
Yield: 52.2 %

Procedure:
To a solution of 4-bromo-N-[(4-chlorophenyl)-methyl]-2,6-diethyl-benzamide (0.34 g, 0.90 mmol) in toluene (3 ml), morpholine (0.11 g, 1.29 mmol), caesium carbonate (0.40 g, 1.22 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.06 g, 0.09 mmol) are added. After degassing with argon for 30 min tris(dibenzylideneacetone)-dipalladium(0) (0.04 g, 0.04 mmol) are added and the mixture is heated at 120° C. for 16 h. After completion of the reaction (monitored by TLC) the mixture is filtered through a pad of celite and diluted with ethyl acetate (30 ml), the organic layer is washed with water and dried over sodium sulfate and concentrated in vacuo. The resulting crude product is purified by preparative HPLC to obtain the N-[(4-chlorophenyl)-methyl]-2,6-diethyl-4-morpholin-4-yl-benzamide (example 41) (0.18 g, 0.47 mmol, 26%). [M+H]+ 387.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-])=O)[CH:16]=2)[CH:9]=1)([O-])=O.[H][H].Cl>C(O)(C)C.[Pd]>[NH2:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=[C:4]([NH2:1])[CH:5]=2)[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Oc2cccc(Oc3cc([N+](=O)[O-])cc(C(F)(F)F)c3)c2)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: Nc1cc(Oc2cccc(Oc3cc(N)cc(C(F)(F)F)c3)c2)cc(C(F)(F)F)c1

Procedure:
Into a reducing device equipped with a thermometer, a reflux condenser and an agitator were charged 72 g of 1,3-bis(3-nitro-5-trifluoromethylphenoxy)benzene (0.147 mol), 500 mL of isopropyl alcohol and 7.2 g of 5%-Pd/C (50% of water content), and the mixture was reacted at 50° C. for 5 hours in an atmosphere of hydrogen. At the end of the reaction, the catalyst was filtered out, the filtrate was condensed under a reduced pressure and the residue was dissolved in 200 g of isopropanol and 400 g of 36% HCl was added to the solution to precipitate the desired hydrochloride. The hydrochloride was suspended in 150 g of water and 200g of 1,2-dichloroethane (EDC), the mixture was neutralized with 28% ammonium hydroxide aq. and separated, and the EDC layer was washed with water and evaporated to give 1,3-bis(3-amino-5-trifluoromethylphenoxy)benzene as a brown viscous liquid; Yield: 33.8 g (53.7%).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.[CH3:10][S:11]SC.N(OC(C)(C)C)=O>C(Cl)Cl>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([S:11][CH3:10])=[CH:3][N:4]=1
Reactant: Nc1cnc(Cl)c(Cl)c1
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CSc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 36.1 %

Procedure:
A solution of 50.6 g (0.3 mol) of 3-amino-5,6-dichloropyridine in 700 ml of methylene chloride was slowly added dropwise at 40° C. to a solution of 56.6 g (0.6 mol) of dimethyl disulfide and 46.7 g (0.45 mol) of tert-butyl nitrite in 320 ml of dry methylene chloride. The mixture was then stirred for 1 hour at 40° C. and subsequently for another approximately 15 hours at approximately 20° C., whereupon 500 ml of ice-water were added to the reaction mixture. The organic phase which was separated off was washed once with 1 N hydrochloric acid and once with water, dried over sodium sulfate and finally concentrated. After the crude product had been stirred with n-hexane, 21 g of a dark solid were obtained (purity 94% according to GC). After the hexane solution was concentrated, a further 21.3 g of product of value remained which had a purity of 77% (according to GC). Total yield: 62%; m.p.: 66-67° C.; 1H-NMR (in d6 dimethyl sulfoxide): δ [ppm]=2.6 (s, CH3); 8.1 and 8.3 (2×d, pyr H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([O:39][C:36]3[CH:37]=[CH:38][C:33]([I:32])=[CH:34][CH:35]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: Oc1ccc(I)cc1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccc(I)cc3)n2)cc1Cl
Temperature: 80 °C
Yield: 90.1 %

Procedure:
A mixture of compound 133 (2.0 g, 5.22 mmol), potassium carbonate (3.6 g, 26.10 mmol) in dimethylformamide (10 mL) was added 4-iodophenol (1.38 g, 6.26 mmol). It was heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound as white solid (2.66 g, 90%). mp 80-82° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 38.47 min, 97.83% purity; MS (CI): m/z 566 (M+H, 100).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:16][C:17]([NH2:19])=O)=[C:9]3[N:14]([CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>ClC(Cl)C.C(Cl)Cl.O>[C:17]([CH2:16][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:15]([C:27](=[O:30])[CH2:28][CH3:29])[N:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2)#[N:19]
Reactant: NC(=O)Cc1c(-c2ccccc2)cn2ccccc12
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCC(=O)c1c(-c2ccccc2)c(CC#N)c2ccccn12
Temperature: 70 °C

Procedure:
2-(2-Phenylindolizin-1-yl)acetamide (1.0 g, 40 mmol) was dissolved in dichloroethane (35 mL) containing triethylamine (0.65 mL). To the stirred solution was added propionyl chloride (0.70 mL). The reaction mixture was heated in an oil bath (70° C.) over the weekend. After cooling, the reaction mixture was diluted with methylene chloride and water. The phases were separated and the aqueous phase was extracted with methylene chloride 3 times. Evaporation of the combined organic layers gave a residue which was purified by column chromatography on silica gel eluting with 1.0-1.2% methanol in methylene chloride to give 115 mg of 1-cyanomethyl-3-propionyl-2-phenylindolizine. The cyanomethyl keto indolizine was reduced to the title compound with lithium aluminum hydride (150 mg) in ethyl ether under reflux in a nitrogen atmosphere overnight. After cooling the reaction mixture was quenched with Rochelle salt and stirred to give a solution. The phases were separated and the aqueous phase was extracted with ether and then made basic with 2.5 N NaOH. The crude product was extracted into methylene chloride and the solvent removed under reduced pressure to give a residue which was purified on silica gel eluting with 9% methanol in methylene chloride to give 70 mg of the free base of the title compound. The free base was dissolved in ethanol to which an ethanolic solution of 70 mg of fumaric acid was added. The solution was evaporated and the residue was recrystallized from methyl ethyl ketone to give the fumaric acid salt of the title compound, mp: 169-172° C.; MS [M+H]+ 279 m/z; Microanalysis was consistent for C19H22N2+C4H4O4+0.7 H2O
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C:3]([C:5]1[CH:37]=[CH:36][C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:23][C:13]3[NH:14][C:15]([C:17]4C=C[CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)=[O:4].[S:39]1C=CN=C1C=O>>[CH3:1][N:2]([CH3:38])[C:3]([C:5]1[CH:37]=[CH:36][C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:23][C:13]3[NH:14][C:15]([C:17]4[S:39][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2Oc2ccccc2S(C)(=O)=O)cc1
Reactant: O=Cc1nccs1
Product: CN(C)C(=O)c1ccc(Oc2cc3nc(-c4nccs4)[nH]c3cc2Oc2ccccc2S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 1 (step 4) or in accordance with the method or by combining it with an ordinary method but using 4-(4-dimethylcarbamoyl-phenoxy)-5-(2-methanesulfonyl-phenoxy)-benzene-1,2-diamine obtained in Example 20 and thiazol-2-carboxaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)[CH3:22]>CN(C=O)C>[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:32])=[CH:26][CH:25]=1)[CH3:22]
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: CCOc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: CCOc1ccc(NC(=O)N2CCC(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Yield: 20.2 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (30 mg, 0.110 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-ethoxy-4-isocyanato-benzene (26.8 mg, 0.164 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a light brown solid (9.7 mg, 20%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.41 (m, 1H), 7.26 (m, 3H), 6.87 (m, 2H), 6.29 (br s, NH), 4.30-4.25 (m, 2H), 4.08 (s, 6H), 4.01 (q, 2H), 3.61 (m, 1H), 3.17 (m, 2H), 2.17 (m, 2H), 2.02-2.01 (m, 2H), 1.40 (t, 3H); LC/MS (ESI): calcd mass 436.2, found 437.3 [M+1]+.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:28]([N:30]([CH2:40][C:41]3[C:42]4[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=4[S:44][CH:45]=3)[C@@H:31]([CH3:39])[CH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:18][C@H:19]([C:28]([N:30]([CH2:40][C:41]1[C:42]2[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=2[S:44][CH:45]=1)[C@@H:31]([CH3:39])[CH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
(S)-tert-Butyl 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-4-oxobutanoate (Compound III-18) 18.5 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 10.2 g, (yield 81%).
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][N:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:18])[C:12]([O:14]C)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O.Cl>[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][N:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:18])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C(CN(C)Cc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)c(Cl)c1)CC(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
Lithium hydroxide (55 mg) was added to a solution of the product of step (a) (722 mg) in tetrahydrofuran/water (30 ml). The mixture was stirred at room temperature for 4 hours, diluted with hydrochloric acid (1M, 50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless foam (301 mg). NMR δH (250 MHz, CDCl3) 1.43 (9H, s), 2.59 (3H, s), 2.90 (1H, m), 3.22 (1H, m), 3.77 (1H, m) 4.10 (1H, m), 4.26 (1H, m),5.67 (1H, br s) 7.24 (1H, dd, J=11.0 and 1.0 Hz), 7.68 (2H,m). m/e (CI+) 377 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([CH3:22])([O-:21])=[O:20]>O>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:12])([CH2:22][N+:19]([O-:21])=[O:20])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Solvent: O
Product: O=C1N(Cc2ccccc2)c2ccccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 11 h

Procedure:
N-benzyl isatin (0.118 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 11 hours. The obtained product was extracted with ethyl acetate and the solvent was removed to give pure product.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][S:7][CH2:6][N:5]1C(OC(C)(C)C)=O)=[O:3].[ClH:16]>C(OC(=O)C)C>[ClH:16].[S:7]1[CH2:8][C@@H:4]([C:2]([NH2:1])=[O:3])[NH:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H]1CSCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl (4R)-4-(aminocarbonyl)-1,3-thiazolidine-3-carboxylate (23 g, 0.1 mol) in ethylacetate (50 mL) at 0° C. was added dry HCl in ethylacetate (3.5 N, 250 mL). The resulting mixture was stirred at room temperature for 2 h, the volatiles were removed under reduced pressure and the residue was triturated with ethylacetate several times to obtain (4R)-1,3-thiazolidine-4-carboxamide hydrochloride salt as an off-white powder (16.5 g) quantitatively. M.R, 201.8-203.9° C.; m/z (M+1), 133; IR cm−1 3387, 3250, 3189, 2857, 1706, 1675, 1612, 1371, 1123, 894; 1H NMR (DMSO-d6) 300 MHz δ 10.30-9.60 (s (br), ½H), 8.10 (s (br), ½H), 7.77 (s (br), 1H), 4.40 (t, J=7.0 Hz, 1H), 4.31 (d, J=9.6 Hz, 1H), 4.25 (d, J=9.6 Hz, 1H), 3.50-3.30 (m, 1H), 3.15 (dd, J=7.0, 11.7 Hz, 1H).
Reaction SMILES: O=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1cc2cccnc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc2cccnc2nc1Cl
Temperature: 0 °C
Yield: 55 %

Procedure:
Ethyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (405.0 mg, 1.86 mmol) was suspended in POCl3 (4.5 ml) under N2. The mixture was heated to reflux for 1.5 h, and then it was allowed to cool down and carefully poured over an ice-water mixture. The mixture was neutralized with solid NaOH and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (CH2Cl2/MeOH 97:3→95:5) to give 242.6 mg (55%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[Cl:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[Cl:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Product: CC(C)(C)OC(=O)NCCOc1ccc(N)cc1Cl

Procedure:
The product was obtained analogously to Intermediate product 29b starting from 2.25 g (7.10 mmol) N-tert.butoxycarbonyl-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-amine by hydrogenation with 500 mg Raney nickel at 3 bar.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=C[C:14]([C:17]3[C:18](C(OC(C)(C)C)=O)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:43]([NH:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)=[O:44])[CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].F[C:53](F)(F)[C:54]([OH:56])=[O:55]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[C:53]([C:54]([OH:56])=[O:55])[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:43]([NH:45][CH:46]3[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]3)=[O:44])[CH2:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCc3ccccc3)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(CCc3ccccc3)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2)c(C(=O)O)c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-N-(2-phenylethyl)-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].F[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1.O>COCCOC.C(OCC)(=O)C>[CH:1]1([O:6][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[C:16]([NH2:29])[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Nc1nc(OC2CCCC2)nc2c1ncn2C1CCCCO1
Temperature: 50 °C
Reaction time: 20 h
Yield: 78.5 %

Procedure:
Cyclopentanol (25 ml, 275 mmol) was added to sodium tert-butoxide (4.05 g, 42.2 mmol) to give a thick suspension which was diluted with 1,2-dimethoxyethane (35 ml) and heated to 50° C. 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.5 g, 10.54 mmol) was added to the resulting solution which was then stirred under nitrogen at 50° C. for 20 hours. The mixture was cooled and water and ethyl acetate were added. The layers separated and the aqueous layer washed again with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure at 40° C. The residue was loaded in cyclohexane (50 ml) onto 330 g silica cartridge and eluted firstly with a 0-100% ethyl acetate in cyclohexane gradient over 10 column volumes and then with a 0-30% methanol in ethyl acetate gradient. Product-containing fractions were combined and evaporated to give the title compound as a white foam (2.51 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14](Br)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: Cc1ccc(N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(Nc2ccc(C)cc2)c2c1C(=O)c1ccccc1C2=O
Reaction time: 6 h
Yield: 82 %

Procedure:
In a reactor were charged p-toluidine (80 parts), 1-methylamino-4-bromoanthraquinone (15.8 parts), sodium acetate (7.5 parts) and copper acetate (0.5 part) and the mixture was kept at 115° to 120° C. for 6 hours under a nitrogen atmosphere. Thereafter, the reaction mixture was diluted with methanol (100 parts) and cooled. The precipitate produced was filtrated, washed with methanol (500 parts) and then water (200 parts), and dried at 80° to 90° C. to obtain 1-methylamino-4-(4'-methylanilino)-anthraquinone (yield 82%).