Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:24][CH:25]1[O:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[CH2:26]1.CC(C)(O)C#N>C(#N)C.ClCCl>[N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([CH:28]1[C:27](=[O:32])[CH2:26][CH:25]([CH3:24])[O:30][C:29]1=[O:31])=[O:7])([O-:3])=[O:2]
Reactant: CC1CC(=O)CC(=O)O1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CC(=O)C(C(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.8 %

Procedure:
2-Nitro-4-trifluoromethylbenzoyl chloride (4 g) was added at 0°-5° C. to a stirred solution of triethylamine (2.2 ml) and 6-methyltetrahydropyran-2,4-dione (2 g) in dry acetonitrile (25 ml) and the mixture was stirred at ambient temperature for 4 hours. Triethylamine (6.4 ml) and acetone cyanohydrin (0.3 ml) were added successively to the solution and the mixture stirred at ambient temperature for a further 2 hours. The mixture was diluted with dichloromethane (50 ml) and washed successively with 2N hydrochloric acid (20 ml) and water (3×20 ml). The dichloromethane solution was dried over sodium sulphate and evaporated under reduced pressure to give a brown gum which was triturated with a mixture of chloroform and hexane (1:1, 20 ml) to give 3-(2-nitro-4-trifluoromethylbenzoyl)-6-methyltetrahydropyran-2,4-dione (2.2 g), mp 135°-136.5° C., as a light cream crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[I:9]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Cl:1][C:2]1[N:7]=[C:6]([I:9])[C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: II
Reactant: Nc1ccc(Cl)nc1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(Cl)nc1I
Temperature: 20 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of 6-chloro-pyridin-3-ylamine (10.0 g, 77.8 mmol) in EtOH (150 mL) was added Ag2SO4 (12.1 g, 38.9 mmol) and I2 (23.7 g, 93.4 mmol) at room temperature. The mixture was stirred at 20° C. overnight. The solvent was removed by evaporation under vacuum. Water (100 mL) and EtOAc (200 mL) were added to the residue. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate 7:1) to give 6-chloro-2-iodo-pyridin-3-ylamine (17.1 g, 86%). 1H NMR (DMSO, 300 MHz) δ 7.16 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 5.57 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:20])[C:5]([O:17][CH2:18][CH3:19])=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH2:12][C:13]([O:15][CH3:16])=[O:14].CCN(CC)CC>CO.[Pd]>[CH2:18]([O:17][C:5]1[C:4]([F:20])=[CH:3][CH:2]=[C:10]2[C:6]=1[C:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][N:9]2[CH3:11])[CH3:19]
Reactant: CCOc1c(F)cc(Cl)c2c1c(CC(=O)OC)cn2C
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOc1c(F)ccc2c1c(CC(=O)OC)cn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A mixture of 30-11 (1.4 g, 4.7 mmol), Pd/C (280 mg, 20%) and Et3N (1.42 g, 14.1 mmol) in MeOH (20 mL) was stirred under hydrogen atmosphere at room temperature overnight. The mixture was filtered and the filtrate was concentrated to afford 30-12 (1 g, 92%) as a yellow solid. LRMS: calc 265.1 and found: 266.1 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[O:10])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][C:21]([C:23]([NH:25][C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(Cl)c3)cc2)o1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 1, using 1-chloro-3-isocyanatobenzene (0.533 mmol) and intermediate 1. 1H NMR (DMSO-d6, 300 MHz): δ 9.056 (s, 1H), 9.013-8.986 (d, 2H), 7.820 (s, 1H), 7.799-7.770 (d, J=8.7 Hz, 2H), 7.728-7.704 (m, 1H), 7.631-7.601 (d, J=9 Hz, 2H), 7.347-7.268 (m, 2H), 7.059-7.024 (m, 1H), 4.328-4.277 (m, 1H), 3.680 (s, 3H), 2.286-2.218 (m, 1H), 0.980-0.958 (d, J=6.6 Hz, 6H); MS (ESI) m/z 469 (M−H), 470 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4](O)=[N:5][CH:6]=[C:7]([Br:9])[CH:8]=1.C1(P(Cl)([Cl:21])=O)C=CC=CC=1>>[Cl:21][C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][C:7]([Br:9])=[CH:6][N:5]=1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Reactant: O=P(Cl)(Cl)c1ccccc1
Product: FC(F)(F)c1cc(Br)cnc1Cl
Temperature: 135 °C
Reaction time: 4 h

Procedure:
The product of Example 5 (11.5 g, 0.048 mol) and phenylphosphoryl dichloride (45 mL) were heated with stirring at 135° C. for four hours and allowed to cool to room temperature. The reaction mixture was poured onto ice (750 g) and allowed to warm to room temperature. The mixture was extracted with dichloromethane (150 mL) and filtered. The organic phase was separated, washed with water and 10% sodium carbonate solution and dried over anhydrous sodium sulphate. Evaporation of the solvent gave 2-chloro-3-trifluoromethyl-5-bromopyridine (11.6 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7](F)[C:6]=1[N+:13]([O-:15])=[O:14])[CH3:2].C(=O)([O-])[O-].[NH4+:21].[NH4+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH2:21])[C:6]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(F)cc(N)c1[N+](=O)[O-]
Yield: 75 %

Procedure:
4.64 g (20 mmol) of 3,5-difluoro-2-nitro-benzoic acid ethyl ester in DMF and 2.1 g (22 mmol) of ammonium carbonate was heated at 60° C. for 6 h. The reaction mixture was treated with water. The resulting solid was collected by filtration and washed with water to produce 3.4 g (15.0 mmol, 75%) of 3-amino-5-fluoro-2-nitro-benzoic acid ethyl ester. LCMS: 229 (M+1)+.
Reaction SMILES: [NH3:1].[O:2]1[C:6]2([CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([NH2:1])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC1CCC2(CC1)OCCO2
Temperature: 5 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Ammonia gas was bubbled into a solution of 1,4-dioxaspiro[4.5]decan-8-one (31.2 g, 199.77 mmol, 1.00 equiv) in methanol (300 mL). The resulting solution was stirred for 8 hrs at 0-10° C. This was followed by the addition of sodium borohydride (11.4 g, 301.35 mmol, 1.51 equiv) in several batches at 0-10° C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 4×300 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 20 g (64%) of 1,4-dioxaspiro[4.5]decan-8-amine as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:1][O:2][C:3]([C:4]1[N:16]=[C:17]([NH2:19])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:15]
Reactant: NC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(Cl)c1
Product: COC(=O)c1nc(N)sc1-c1cccc(Cl)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-chloro-phenyl)-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.82 min; [M+H]+=269.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:18]=[C:17]([NH:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=2)[N:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:20]=[C:19]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])[N:18]=[C:17]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=2)[N:16]=1
Reactant: COC(=O)c1ccc(Nc2nc(NCCCOCCCCOCCCN)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NCCCOCCCCOCCCNc1nc(Nc2ccc(C(=O)O)cc2)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
To a suspension of methyl 4-(4-(3-(4-(3-aminopropoxy)butoxy)propylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.1 g) in acetone (6 mL) was added potassium carbonate in water (6.00 mL). The mixture was heated to reflux for 16 hours. After cooling to r.t., the reaction solution was acidified with 1N HCl to pH=3. All the solvents were removed under vacuum. The residue was purified by prep. HPLC to give 4-(4-(3-(4-(3-aminopropoxy)butoxy)propylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (28 mg, 0.054 mmol).
Reaction SMILES: [CH2:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][C@H:6]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:5]1)[CH2:2][CH3:3].S(Cl)([Cl:30])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:30][C:15]1[NH:14][C:13]2[C:19]3[C:16]=1[CH2:17][C@@H:18]1[C@@H:8]([C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:7][C@H:6]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:5][N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCN1C[C@@H](NC(=O)C(C)(C)C)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCN1C[C@@H](NC(=O)C(C)(C)C)C[C@@H]2c3cccc4[nH]c(Cl)c(c34)C[C@H]21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1 g silica gel are added to 2 g 6-n-propyl-8α-pivaloylamino-ergoline (example 2) in 50 ml methylene chloride, pre-cooled to 0° C. 0.503 ml sulfurylchloride are added drop-wise and the reaction mixture stirred for 4 hours. 1N potassium carbonate solution is added, the mixture extracted with methylene chloride, dried over Na2SO4 and concentrated. The residue is chromatographed on 50 g silica gel using toluene/ethylacetate (2:1) as eluant to yield the title compound. M.P.=146°-147° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[N:13]1[CH:9]([CH2:10][CH:11]([O:26]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:12]1)[C:8](=[O:38])[NH:7]2)=[O:5])[CH3:2].[OH-].[Li+].C(O)(=O)C>CO.C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[N:13]1[CH:9]([CH2:10][CH:11]([OH:26])[CH2:12]1)[C:8](=[O:38])[NH:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(OC(=O)c3ccc([N+](=O)[O-])cc3)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(O)CC1C(=O)N2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Compound 50 (200 mg, 0.38 mmol) was dissolved in a mixture of methanol/THF/water, 1:2:1, (20 ml) and cooled on ice-bath. Lithium hydroxide (1.9 ml, 1M) was added slowly. The mixture was stirred for 4 h at 0° C., then neutralized with aqueous acetic acid (20 ml) and extracted with dichloromethane. The organic phase was washed with bicarbonate, water, brine and dried over magnesium sulfate. Purification by chromatography (2% methanol in dichloromethane→4%) gave the title compound as a greyish powder (80%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCCC1>C(O)C>[CH2:1]([NH:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:24]3\[C:25](=[O:30])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[CH:29][CH:28]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCNCCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCNCCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 90 °C
Yield: 80.9 %

Procedure:
5-(2-Ethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 62j (45 mg, 0.118 mmol) was dissolved in 5 ml of ethanol under stirring, and added with 5-fluoro-1,3-dihydro-indol-2-one (16 mg, 0.106 mmol) and piperidine (0.15 ml, 1.49 mmol) to the solution. Upon completion of the addition, the reaction mixture was refluxed at 90° C. in an oil bath for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure, added with a little ethanol, and filtered to obtain the title compound (Z)-5-(2-ethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 62 (34 mg, yield 76%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]3N[CH:10]([C:16]4[S:20][C:19]([CH:21]([CH3:23])[CH3:22])=[N:18][CH:17]=4)[CH2:11][C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH3:25].[CH2:26]1COCC1>O=[Mn]=O>[OH:15][C:12]1[C:13]2[O:14][C:6]3[CH:5]=[CH:4][C:3]([O:24][CH3:25])=[C:2]([Br:1])[C:7]=3[C:8]=2[CH:26]=[C:10]([C:16]2[S:20][C:19]([CH:21]([CH3:23])[CH3:22])=[N:18][CH:17]=2)[CH:11]=1
Reactant: COc1ccc2oc3c(c2c1Br)NC(c1cnc(C(C)C)s1)CC3=O
Reactant: C1CCOC1
Agent: O=[Mn]=O
Product: COc1ccc2oc3c(O)cc(-c4cnc(C(C)C)s4)cc3c2c1Br
Temperature: 110 °C
Yield: 73 %

Procedure:
A mixture of 14B (1.1 g, 2.6 mmol), MnO2 (6 g) in THF (20 mL) was heated to 110° C. and reacted overnight, then filtered. The filtrate was concentrated to give 14C (0.8 g, 73% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:2]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[C:12]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:1]2[CH:5]=[N:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:2]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cc1nc[nH]n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
Ethyl (1H-1,2,4-triazol-3-yl)acetate (2.83 g) was dissolved in DMF (40 ml). To the solution were added triphenyl methyl chloride (5.08 g) and triethylamine (2.55 ml). The mixture was stirred for 3 hours at 25° C. The reaction mixture was added to ice-water (150 ml), which was subjected to extraction with ethyl ether (100 ml). The organic layer was washed twice with water (150 ml), which was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: silica gel, 150 g, developing solvent: ethyl acetate-hexane, 1:1) to afford the title compound (2.56 g) as a crystalline product, m.p.117-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](C)[CH:13]=1)=[C:5]2[CH2:20][C:21]([OH:23])=[O:22].BrC1C=CC([Cl:31])=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:31])=[CH:14][CH:13]=1)=[C:5]2[CH2:20][C:21]([OH:23])=[O:22]
Reactant: Cc1cccc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Reactant: Clc1ccc(Br)cc1
Product: O=C(O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 5-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 18, step 1) and 4-bromochlorobenzene.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C[O-].[Na+].[CH2:8]([N:11]([CH:17]([CH3:20])[CH:18]=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH2:10].O>CO.C1(C)C=CC=CC=1>[CH3:2][N:3]1[O:4][CH2:10][CH:9]2[CH:18]1[CH:17]([CH3:20])[N:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]2
Reactant: C=CCN(C(=O)OCC)C(C)C=O
Reactant: CNO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)N1CC2CON(C)C2C1C

Procedure:
A methanolic methylhydroxylamine solution is prepared from 16.4 g (0.2 mol) of N-methylhydroxylamine hydrochloride in 33 ml of absolute methanol and 36 g (0.2 mol) of 30% strength sodium methylate solution, and the solution formed is diluted with 130 ml of toluene and added dropwise to 354 g (0.17 mol) of N-allyl-N-(1-oxoprop-2-yl)-urethane in 250 ml of toluene, which is heated under reflux using a water separator. The mixture is heated under reflux overnight, the product is extracted with dilute hydrochloric acid and the hydrochloric acid solution is rendered alkaline with K2CO3 and extracted with CHCl3. The extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:23](=[O:25])[CH2:22][O:21][C:18]2[CH:19]=[N:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)COc1ccc(-c2ccc(F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccc(F)cc2)nc1)Nc1ccc(F)cc1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 43.8 mg (0.39 mmol) of 4-fluoroaniline. Yield: 31 mg.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>C(OCC)(=O)C>[C:4]([C:3]1[N:9]=[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]2[CH:2]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=O)CBr
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cn2cc([N+](=O)[O-])ccc2n1

Procedure:
Operations similar to Production Example 1-(2) were conducted using 1-bromopinacolone and 2-amino-5-nitropyridine. The solid whereupon obtained was suspended in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate solution to provide the title compound as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH3:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH2:9][CH2:10][CH3:11])[CH:4]=1
Reactant: BrCCCCCBr
Reactant: CCCc1cc(S)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1cc(SCCCCCBr)ccc1C
Yield: 291.1 %

Procedure:
A mixture of 36.5 g of 4-methyl-3-n-propylthiophenol, 11.5 g of 1,5-dibromopentane, 80 ml of water, 0.5 g of tetrabutylammonium bromide and 10 ml of toluene was stirred drastically and heated at 80° to 90° C. At this temperature, a solution of 8.6 g of sodium hydroxide and 20 ml of water was added dropwise to the mixture during 1 hour. The reaction was finished by stirring for 2 hours after the dropwise addition. After cooling, the reaction mixture was added with 150 ml of toluene, and separated to layers. A toluene layer was washed with water, and dried over anhydrous sodium sulfate. Then, the residue obtained by distilling off toluene and an excess of 1,5-dibromopentane under reduced pressure, was purified by silica-gel column chromatography (developing solvents: toluene+n-hexane) to give 45.9 g of the intended 1-bromo-5-(4-methyl-3-n-propylthiophenoxy)-n-pentane (yield: 69.3%) as a colorless oil. nD25 1.5569.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N+:8]([O-:26])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: ClCCl
Product: CN1C(=O)C[N+]([O-])=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
5.70 g (20 mmol) of 7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)on (manufactured by Sigma, No. T 8275) are dissolved in 150 ml of dichloromethane and 13.8 g (40 mmol) of 3-chloro-peroxybenzoic acid (manufactured by Aldrich, No. 27.303-1) are added under stirring at 20° C. Stirring of the solution is continued for 1.5 h at 20° C. Then the reaction mixture is washed first with 200 ml of 5% NH3 and subsequently with 200 μl of 0.1 n NaOH. The solvent is removed on an rotatione evaporator and the remaining oily residue is dissolved in 25 ml of isopropanol under heating to 40°-45° C. Subsequently, the product is allowed to crystallize under slow cooling down to room temperature. 2 hours after the onset of crystallization, the solid product 2 is drawn off and washed with 50 ml of isopropanol and 50 ml of diisopropylether. The mixture is then dried over night over paraffin in an exsiccator.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][N:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.[K+].[Br-]>>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[C:10](=[N:9][N:8]=3)[CH:11]=[C:12]3[O:13][CH2:1][O:2][C:3]3=[CH:4]4)[N:14]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(CCN2CCCC2)c2cnnc3cc4c(cc23)OCO4)cc1OC
Agent: [Br-]
Agent: [K+]
Product: COc1cc2c(=O)n(CCN3CCCC3)c3c4cc5c(cc4nnc3c2cc1OC)OCO5
Yield: 24 %

Procedure:
Prepared from N-(6,7-Methylenedioxycinnolin-4-yl)-N-[(2-pyrrolidin-1-yl)ethyl]-2-iodo-4,5-dimethoxybenzamide (150 mg, 0.2 mmol) in 24% yield with a reaction time 30 min; mp 229° C.; IR (KBr) 1644; 1H NMR (CDCl3) δ 1.83 (m, 4H), 2.71 (m, 4H), 3.23 (t, 2H, J=7), 4.06 (s, 3H), 4.61 (s, 3H), 4.63 (t, 2H, J=7), 6.23 (s, 2H), 7.74 (s, 1H), 7.80 (s, 1H); 13C NMR (CDCl3) δ 23.7, 54.0, 54.2, 56.3, 56.6, 99.4, 102.7, 104.2, 106.3, 107.7, 113.5, 119.4, 129.0, 134.1, 140.2, 150.2, 151.4, 154.3, 154.3, 163.0; HRMS calcd for C24H24N4O5H: 449.1825; found 449.1822.