Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](Br)[CH:14]=[C:15]4[O:19][CH2:18][O:17][C:16]=34)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]([C:26]4[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=4)[CH:14]=[C:15]4[O:19][CH2:18][O:17][C:16]=34)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(-c2cc3c(c(C45CC6CC(CC(C6)C4)C5)c2)OCO3)cc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A mixture of 3-(1-adamantyl)-4,5-methylenedioxy-1-bromobenzene (2.00 g, 5.97 mmol), 4-formylphenylboronic acid (1.07 g, 7.16 mmol) and potassium carbonate (1.86 g, 13.42 mmol) in 1,2-dimethoxyethane (50 mL) and water (2.5 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.298 mmol) was added and the mixture heated at reflux under argon overnight. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:ethyl acetate, 95:5) to give 1.82 g of 4-[3-(1-Adamantyl)-4,5-methylenedioxy phenyl]-benzaldehyde (85%). 1H NMR (500 MHz; CDCl3): δ 1.79 (s, 6H); 2.08 (s, 9H); 6.01 (s, 2H); 7.00 (d, J=2.0 Hz, 1H); 7.04 (d, J=2.0 Hz, 1H); 7.68 (d, J=8.1 Hz, 2H); 7.91 (d, J=8.1 Hz, 2H); 10.03 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Product: O=[N+]([O-])c1cc(F)ccc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,5-difluoronitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([N:5]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:4].O1CCOCC1.O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46].C1(N=C=NC2CCCCC2)CCCCC1>O.CCCCCC>[F:1][C:2]([F:31])([F:32])[C:3]([N:5]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([O:28][N:40]2[C:44](=[O:45])[CH2:43][CH2:42][C:41]2=[O:46])=[O:27])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:4]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: O
Product: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1

Procedure:
To stirred ice-cold solution of 18.3 g. of p-(2,2,2-trifluoro-N-hexadecylacetamido)benzoic acid in 80 ml. of dioxane is added successively 4.84 g. of N-hydroxysuccinimide and 9.16 g. of dicyclohexylcarbodiimide. After 18 hours at 0°-5° C. the mixture is stirred vigorously for one hour with hexane and water and filtered. The hexane layer is washed with water, dried over magnesium sulfate, and concentrated to give an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.C(C1C=CC(CC[NH2:24])=CC=1)C.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[C:7]([NH2:24])(=[O:8])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:10]=1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCc1ccc(CCN)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)c1ccccc1

Procedure:
A solution of 4.1 g of 5-chloro-2-methoxy-benzoyl chloride in 20 ml of toluene was added dropwise to a suspension of 4.65 g of 2-(4-ethylphenyl)-ethylamine hydrochloride in 100 ml of anhydrous toluene after addition of 5 ml of pyridine. The whole was heated under reflux, then shaken with water, dilute hydrochloric acid and a solution of sodium bicarbonate and dried over sodium sulfate. After concentration under reduced pressure, the residue, which solidified only slowly, was filtered off with suction after addition of petroleum ether (B.p. 30°-60° C.). The 5-chloro-2-methoxy-N-(2-<4-ethylphenyl>-ethyl)-benzamide so obtained was found to melt at 66°-68° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:25][CH2:26]2)=[O:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(COC(=O)N2CCN(c3ccccc3)CC2)C1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
2-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (4.13 g, 19.0 mmol) was dissolved in anhydrous THF (20 mL) and the solution cooled to 0° C. NaH (60% wt dispersion in oil; 2.28 g, 57.0 mmol) was added and the grey suspension stirred for 10 minutes before 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 7.46 g, 22.8 mmol) was added. The reaction was stirred at room temperature over the weekend. A further 1.5 equivalents of NaH (60% wt dispersion in oil) (1.14 g, 28.5 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched with sat aq NaHCO3 solution (50 mL) before the THF was removed in vacuo. The organic product was extracted with EtOAc (3×50 mL) and the organic layers combined, washed with sat aq NaHCO3 solution (3×50 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×36 mm (200 g), 30 mL/min, gradient 0% to 80% (over 120 mins) MeOH in water with 1% formic acid) to afford 2-(4-phenylpiperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (6.67 g, 87% yield) as a dark brown oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:22][O:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>>[CH3:22][O:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)(=[O:3])=[O:4].[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: COc1ccccc1N
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: COc1ccccc1NS(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 21.6 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 62 μL (0.55 mmol) of 2-methoxyaniline. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5) then trituration in diethyl ether, 22 mg (11%) of 8-(2-methoxy-phenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][NH:19][S:20]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[CH:17][C:12]=2[O:11][CH2:10]1>O1CCCC1>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][NH:19][S:20]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31]([NH:2][OH:3])=[O:32])[CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.37 g, 5.40 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-{3-[(benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride (0.41 g) in tetrahydrofuran (4 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate and washed with diethyl ether affording the title compound (0.14 g, 35%). M.p. 163° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.92 (2H, d, J=6.4 Hz); 5.92 (2H, s); 6.49 (1H, d, J=16.0 Hz); 6.67 (3H, s); 7.34-7.89 (5H, m); 8.12 (1H, t, J=6.4 Hz); 9.07 (1H, br s); 10.78 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 3.5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 30:70; sample concentration 0.25 mg/ml; flow rate 1.2 ml/min; detector UV 254 nm). Anal. Calcd for C17H16N2O6S, %: C 54.25, H 4.28, N 7.44. Found, %: C 54.19, H 4.20, N 7.33.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1.O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:9]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
140 ml of benzylbromide are added dropwise to a mixture of 61 g of trans-4-amino-cyclohexanol, 350 ml of water, 350 ml of ethanol and 110 g of potassium carbonate. The mixture is then heated to boiling for 1 hour, cooled and the crystalline residue is suction filtered. The residue is taken up in 1.51 of cyclohexane, the mixture is boiled, cooled and suction filtered. Washing with cyclohexane and drying in vacuo yields 108 g (92% of theory) of trans-4-dibenzylamino-cyclohexanol.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([O:21]CC)=O)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][NH2:25]>C(O)C>[C:1]1([CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]([NH:24][NH2:25])=[O:21])[CH2:16][CH2:17]2)[C:2]2[C:7](=[CH:8][CH:9]=[CH:4][CH:3]=2)[CH:6]=[CH:5][CH:10]=1
Reactant: CCOC(=O)CN1CCN(Cc2cccc3ccccc23)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2cccc3ccccc23)CC1

Procedure:
Synthesized according to General Procedure C: 6{24} (8.29 g, 26.5 mmol, 1 equiv.), anhydrous hydrazine (2.5 mL, 79.6 mmol, 3 equiv.), ethanol (53.4 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{24} (6.86 g, 87%) as a brown oil. 1H-NMR (500 MHz, CDCl3): δ 8.70 (d, 1H, J=8.0 Hz), 8.19 (br s, 1H), 7.84 (d, 1H, J=7.5 Hz), 7.77 (dd, 1H, J=3.0, 6.5 Hz), 7.52-7.46 (m, 2H), 7.41-7.38 (m, 2H), 3.90 (s, 2H), 3.87 (br s, 2H), 3.06 (s, 2H), 2.51 (br s, 8H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 133.7, 133.7 132.4, 128.3, 127.9, 127.3, 125.6, 125.5, 125.0, 124.6, 60.9, 60.5, 53.6, 53.2.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:15][C:14]([F:17])([F:16])[CH2:13][NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)NCC(F)(F)F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=S)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
Slurry 1-benzoyl-3-(2,2,2-trifluoroethyl)-thiourea (5.5 g, 21.2 mmol) and potassium carbonate (11.7 g, 84.7 mmol) in methanol (180 mL) and water (40 mL). Stir the mixture at room temperature for 16 h. Concentrate the solution in vacuo to a paste. Triturate with hot water (20 mL, 60° C.), filter off the solids, wash with water (20 mL, 25° C.) and hexane (excess). Collect the solids, slurry in EtOAc and concentrate in vacuo twice to remove residual water. Dry the material in a vacuum oven at 45° C. for 16 h to obtain the desired intermediate as an off-white solid (2.2 g, 66%). MS (ES+) m/z: 159.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CC(C)C(=O)Nc1ccc2[nH]ccc2c1
Product: CC(C)C(=O)Nc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate 06) and N-(1H-indol-5-yl)isobutyramide (intermediate 10).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:2]3[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:26]=2)=[O:41])[CH2:21][CH2:22]1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)nc2)c1

Procedure:
6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.94 min, MH+ 416. NMR: δH [2H6]-DMSO 9.29,(1H, t), 9.15,(1H, s), 8.48,(1H, d), 8.35,(1H, d), 7.89,(1H, s), 7.81,(1H, d), 7.72, (1H, d), 7.41,(1H, d), 7.26,(1H, t), 6.93,(2H, m), 6.84,(1H, s), 4.51,(2H, d), 3.75, (3H, s), 2.86,(1H, m), 2.38,(3H, s), 0.69,(2H, m), 0.57,(2H, m).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][C:12]=2[CH:15]=1
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Br)ccc2o1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
13.8 g (100 mmol) Na2CO3 are added to a solution of 4.02 g (20.0 mmol) 5-bromo-salicylaldehyde and 2.26 mL (20.0 mmol, 98%) ethyl bromoacetate in 50 mL DMF. The reaction mixture is heated to 80° C. and stirred for 2 h at this temperature. It is diluted with 200 mL water, the aqueous phase is extracted three times with 100 mL tert-butylmethylether and the combined organic extracts are washed twice with 50 mL water. The organic phase is dried over MgSO4, filtered through activated charcoal and the solvent is eliminated i.vac.
Reaction SMILES: COC(=O)C[NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45](N)=[CH:44][CH:43]=1>CCCCCCC.C(OCC)(=O)C>[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:9][C:8]=2[Cl:36])=[CH:44][CH:43]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 4-amino-benzoic acid methyl ester (commercially available, CAS RN 619-45-4) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light brown foam (29%). MS (ESI): m/z=617.136 [M+H]+.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:15]=1)[CH:11]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:23]([C:25]1[CH:47]=[CH:46][C:28]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43](=[O:45])[CH3:44])=[CH:27][CH:26]=1)=O.[NH:48]1[CH:52]=[CH:51][CH:50]=[CH:49]1>>[C:43]([O:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:28]1[CH:46]=[CH:47][C:25]([C:23]2[C:52]3[NH:48][C:49]([C:11]([C:10]4[CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:15]=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=4)=[C:49]4[N:48]=[C:52]([C:11]([C:10]5[CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:15]=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=5)=[C:52]5[NH:48][C:49](=[C:11]([C:10]6[CH:9]=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]=6)[C:49]6[CH:50]=[CH:51][C:52]=2[N:48]=6)[CH:50]=[CH:51]5)[CH:51]=[CH:50]4)=[CH:50][CH:51]=3)=[CH:26][CH:27]=1)(=[O:45])[CH3:44]
Reactant: c1cc[nH]c1
Reactant: CC(=O)OCCCCCCCCCCCCOc1ccc(C=O)cc1
Reactant: CCCCCCOc1cc(C=O)cc(OCCCCCC)c1
Product: CCCCCCOc1cc(OCCCCCC)cc(-c2c3nc(c(-c4cc(OCCCCCC)cc(OCCCCCC)c4)c4ccc([nH]4)c(-c4cc(OCCCCCC)cc(OCCCCCC)c4)c4nc(c(-c5ccc(OCCCCCCCCCCCCOC(C)=O)cc5)c5ccc2[nH]5)C=C4)C=C3)c1

Procedure:
The title compound was prepared according to the method described in Example 15 above from 3,5-dihexyloxy-benzaldehyde (see Example 12), acetic acid 12-(4-formyl-phenoxy)-dodecyl ester (see Example 6) and pyrrole.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH3:18][C:19]([CH3:23])=[CH:20][CH2:21]Br.[In].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:19]([CH3:23])([CH3:18])[CH:20]=[CH2:21])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: CC(C)=CCBr
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: Cl
Agent: [In]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(C)(C)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.31 g; 1.09 mmol), 3,3-dimethylallyl bromide (90%; 1.40 mL; 10.8 mmol) and indium (1.26 g; 11.0 mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL) and stirred vigorously over 18 hours. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude oil. The crude oil was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[NH4+].[SH:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21].ClC(Cl)(Cl)C(O)=O>O>[NH4+:6].[Cl:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][Cl:15])[P:4]1(=[O:5])[NH:6][CH:7]([S:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21])[CH2:1][CH2:2][O:3]1
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: O=S(=O)([O-])CCS
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH4+]
Solvent: O
Product: O=P1(N(CCCl)CCCl)NC(SCCS(=O)(=O)[O-])CCO1
Reaction time: 72 h

Procedure:
2.8 g (10 mmol) of 4-hydroxycyclophosphamide and 1.6 g (10 mmol) of ammonium-2-mercaptoethanesulphonate were dissolved together with a catalytic quantity of trichloroacetic acid in 50 ml of water and were left to stand in a refrigerator for 3 days at 0° C. The water was then distilled off under high vacuum, the residue was taken up twice in acetone and concentrated under vacuum. Recrystallisation from acetone/ether.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 3-Chlorophenyl isocyanate (0.03 mL, 0.26 mmol) was added dropwise, and the reaction solution was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (1 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 32 (54 mg, 56% yield) as a yellow solid. LC-MS (M+H=361, obsd.=361).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:7]=1.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:19][CH2:18]2)[N:7]=1
Reactant: O=c1c2ccccc2c(Cc2ccc(Cl)c(Cl)c2)nn1C1CCCNCC1
Reactant: ClCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=c1c2ccccc2c(Cc2ccc(Cl)c(Cl)c2)nn1C1CCCN(Cc2ccccc2)CC1

Procedure:
A solution of 3.28 grams (8.15 mmoles) of 4-(3,4-dichlorobenzyl)-2-(hexahydro-1H-azepin-4-yl)-1-(2H)-phthalazinone, 3.4 ml (29.5 mmol) of benzyl chloride and 9 ml (64.6 mmol) of triethylamine in 20 ml of dioxane were heated for 12 hours at 200° C.