Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:15]1[O:23][C@@H:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[OH:23][C@H:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: NCCCc1ccc(S(N)(=O)=O)cc1
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(CCCNC[C@H](O)c2ccccc2)cc1
Yield: 26.6 %

Procedure:
A mixture of 20.0 g of 3-(4-aminosulphonylphenyl)-propylamine, 16.8 g (R)-styrene oxide and 500 ml of acetonitrile was heated under reflux for 40 hours. The solvent was then evaporated in vacuo and the residue was chromatographed on 1 kg of silica gel, using with chloroform/n-propanol/25% ammonia (1600:100:4). There was isolated 8.3 g of pure p-[3-[[(R)-β-hydroxyphenethyl]amino]propyl]-benzenesulphonamide of melting point 165°-166° (from acetonitrile). [α]D20 =-13.4° (c=1.0% in methanol); UV: ε224 =14710.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:24][CH2:25][CH3:26])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18].CN(C)P(N(C)C)(N(C)C)=O>O>[C:1]1([O:11][CH2:12][CH2:13][NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]([O:24][CH2:25][CH3:26])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCOc1cccc2ccccc12
Reactant: CCOC(=O)c1ccccc1N
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccccc1NCCOc1cccc2ccccc12

Procedure:
A solution of 12.54 g. of 2-(1-naphthyloxy)ethyl bromide and 16.5 g. of ethyl anthranilate in 50 ml. of hexamethylphosphoramide are heated at 110° for 18 hours. After cooling and diluting with water, the mixture is extracted twice with 200 ml. of ether. The combined ether extracts are washed with water, dried and evaporated to a brown oil. The oil is dissolved in 60 ml. of ethanol and chilled in an ice-bath yielding a beige solid which is recrystallized from 100 ml. of ethanol affording pale yellow crystals, m.p. 81°-83° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[N:17]=[C:18]=[O:19]>C1(C)C=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([NH:17][C:10]2[C:11]([Cl:16])=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[Cl:8])=[O:19])=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=C=Nc1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccncc1)Nc1c(Cl)cc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 3 h

Procedure:
4-Aminopyridine (500 mg, 3.56 mmol) and 2,4,6-trichlorophenyl isocyanate (503.6 mg, 3.56 mmol 1.0 moleg), were dissolved in toluene, and the mixture was then stirred at 110° C. for 3 hr.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9]O)=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[Cl:23][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(F)ccc1OCCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OCCCCl
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred mixture of 12.6 parts of 3-(4-fluoro-2-nitrophenoxy)propanol, 0.9 parts of N,N-dimethylformamide and 150 parts of trichloromethane were added dropwise 8.36 parts of thionyl chloride and stirring was continued for 1 hour at room temperature. The whole was further stirred and refluxed for 3 hours. The reaction mixture was evaporated under methylbenzene. The residue was stirred in petroleumether. The product was filtered off and dried, yielding 7.41 parts (55%) of 1-(3-chloropropoxy)-4-fluoro-2-nitrobenzene; mp. 143.3° C. (intermediate 25).
Reaction SMILES: Cl[CH:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH:7]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]3[CH2:5][C:4]=2[NH:3]1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.CCOC(C)=O>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:11]=[CH:10][C:9]4[C:8](=[O:12])[CH:7]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]5[CH2:5][C:4]=4[N:3]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccc(N3CCN(c4ccccc4)CC3)nc2CC2CCCCC12
Yield: 247.4 %

Procedure:
A mixture of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H-benzo[g]quinolin-5-one (0.29 g, 0.123 mmol) and 1-phenylpiperazine (2.0 g, 12.3 mmol) was stirred at 100° C. for 1 h (TLC control; hexane-EtOAc, 2:1). Then the mixture was separated by column chromatography on silica gel to give the title compound (0.11 g, 25%) as a pale yellow solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]1([OH:21])[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:21][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Oc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture (0.06 moles) of 2-chloromethylquinoline hydrochloride, (0.06 moles) of 1,3-benzenediol and 18 g of potassium carbonate in 50 ml of dimethylformamide is heated at 70° C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 2-(3-hydroxyphenoxy)methylquinoline having an m.p. of 151°-53° C.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:14][CH:15]=2)=[CH:7][CH:6]=1.[C:24]1([C:30]2[C:34]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][NH:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[C:24]1([C:30]2[C:34]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:32]([CH2:4][C:5]3[CH:23]=[CH:22][C:8]([O:9][CH2:10][C:11]4[N:12]=[C:13]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[S:14][CH:15]=4)=[CH:7][CH:6]=3)[N:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
Sodium hydride (60%, oily, 110 mg) was added to a solution of 4-(4-chloromethylphenoxymethyl)-2-phenylthiazole (760 mg) and ethyl 3-(3-phenyl-1H-pyrazol-4-yl)propionate (580 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1110 mg, yield: 89%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=CC(S(OCC(C)CC)(=O)=O)=[CH:3][CH:2]=1.[C:17]1([CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:19]=1)[OH:18].[OH-].[Na+]>O.C(O)CCC>[CH3:6][CH:1]([CH2:2][CH3:3])[CH2:16][O:18][C:17]1[CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:19]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCC(C)COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCC(C)COc1ccc(O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Into a n-butanol suspension containing 37 mmol (9.0 g) of 2-methylbutyl p-toluenesufonate prepared by tosylating S-(-)-2-methylbutanol and 74 mmol (8.2 g) of hydroquinone, added dropwise was a solution of 50 mmol (2.1 g) of sodium hydroxide dissolved in a solvent mixture of 3 ml of water and 10 ml of n-butanol. After conclusion of the dropping, the mixture was then stirred for 8 hours at 120° C. After addition of water, the reaction solution was extracted with ether, and the extracted solution was dried and concentrated. The concentrate was purified by column chromatography, to obtain 4.8 g of the objective ether compound (Yield: 72%)
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:13])[CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>[OH-].[Na+].O>[CH3:14][S:15]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:13])[CH:3]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccccc21
Reaction time: 0.25 h

Procedure:
3-Hydroxy-1-methyl-4-quinolone (30 g) was dissolved in a solution of sodium hydroxide (8 g) in water (440 ml). Activated carbon (3 g) was added and the mixture stirred at 40° for 15 minutes. The mixture was filtered and the filtrate cooled in an ice/salt bath at 0 to 5° under nitrogen. Methanesulphonyl chloride (1 5.5 ml) was added dropwise over 30 minutes and the mixture then stirred at 0 to 5° for 30 minutes. Aqueous sodium hydroxide (5M, 40 ml) was added and the mixture stirred at 0 to 5° for a further 90 minutes. The resultant solid was collected by filtration and washed with water (2×50 ml) to yield crude product. The filtrate was treated with further methanesulphonyl chloride (15.5 ml) in a similar manner to that described above to give a second crop of crude product. The two crops of crude product were combined and crystallised from industrial methylated spirit (2 1) to give the novel compound 1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 208°-209°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=O.[CH2:12]([O:14][CH:15]([O:20][CH2:21][CH3:22])[C:16](=[NH:19])OC)[CH3:13]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:10])[NH:19][C:16]([CH:15]([O:20][CH2:21][CH3:22])[O:14][CH2:12][CH3:13])=[N:11]2
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: CCOC(OCC)C(=N)OC
Solvent: CCO
Product: CCOC(OCC)c1nc2cccc(Cl)c2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a stirred solution of 6-chloro anthranilic acid (6 g, 34.97 mmol) in EtOH (60 mL) under nitrogen atmosphere was added 1.5 equivalent of TEA (14 mL, 104.9 mmol). Upon completion of addition, the mixture was heated to 50° C. where it stirred for 30 min. After this time, a methyl 2,2-diethoxyacetimidate (6 g, 41.96 mmol) in ethanol solution was added through syringe and the resulting mixture was heated to reflux where it stirred for 24 h. At the conclusion of this period, the reaction mixture was cooled to RT and the volatiles were evaporated. The resulting residue was diluted with water, extracted with DCM and washed with brine solution. The crude product was purified by column chromatography (25% ethyl acetate in hexane) to provide 5-chloro-2-(diethoxymethyl)quinazolin-4(3H)-one (7 g, 60% yield). LCMS Method W: retention time 1.5 min; [M+1]=283.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:15]4[CH2:19][CH2:18][O:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([O:24]CC)=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:15]4[CH2:19][CH2:18][O:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCOC3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOC3)c(F)cc2c1=O
Reaction time: 1 h
Yield: 66.7 %

Procedure:
A mixture of 182 mg of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-oxazolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 5 ml of ethanol and 10 ml of 10% aq. sodium carbonate solution was stirred for 1 hour under reflux. The reaction mixture was allowed to cool down and then acidified with acetic acid. Crystals thus precipitated were collected by filtration. They were washed with water and ethanol and then dried, whereby 112 mg of the title compound was obtained.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:19][O:20][CH2:21][CH2:22]O.C(P(CCCC)CCCC)CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][C:48](=[O:50])[N:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[OH:57])[CH2:46][C:45]1([CH3:59])[CH3:58])=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1(C)C=CC=CC=1.O>[C:37]([O:41][C:42]([N:44]1[CH2:49][C:48](=[O:50])[N:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[O:57][CH2:22][CH2:21][O:20][CH3:19])[CH2:46][C:45]1([CH3:59])[CH3:58])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2O)CC1(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COCCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
518 mg of 1,1′-(azodicarbonyl)dipiperidine (2.05 mmol), 156 mg of 2-methoxyethanol (2.05 mmol) and 0.42 ml of tributylphosphine (2.05 mmol) were added to a solution of 400 mg of 4-(2-hydroxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10d) (1.36 mmol) in toluene (14 ml), and the mixture was stirred at 100° C. for three hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=1/2) to obtain 444 mg of 4-[2-(2-methoxyethoxy)phenyl]-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester (yield: 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH3:10].[C:11](OCC)(=[O:13])[CH3:12].C(N)(=O)C>CCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:11](=[O:13])[CH3:12])=[CH:5][C:4]=1[CH3:10]
Reactant: COc1ccc(N)cc1C
Reactant: CCOC(C)=O
Agent: CC(N)=O
Solvent: CCCCC
Product: COc1ccc(NC(C)=O)cc1C

Procedure:
By proceeding in a manner similar to Reference Example 33(a) above but using 4-methoxy-3-methyl-phenylamine (2.07 g, Reference Example 30(u)) and subjecting the reaction product to flash chromatography on silica eluting with a mixture of ethyl acetate and n-pentane (1:1, v/v) there was prepared N-4-methoxy-3-methyl-phenyl)-acetamide (2.65 g) as a pale pink crystalline solid. LC-MS (Method J): RT=2.94 minutes, 180.30 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12](=[S:15])[NH:13][N:14]=1.Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CCO.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:14][N:13]=[C:12]([S:15][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:11]=1
Reactant: BrCc1ccccn1
Reactant: COc1cc(C)ccc1-c1n[nH]c(=S)[nH]1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C)ccc1-c1nc(SCc2ccccn2)n[nH]1
Temperature: 60 °C
Yield: 72 %

Procedure:
To a solution of 5-(2-methoxy-4-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (Example 1a) (110 mg, 0.5 mmol) in 2 ml of EtOH was added 2-(bromomethyl)pyridine hydrobromide (152 mg, 0.6 mmol). The suspension was heated at 60° C. for 22 h. The reaction was diluted with EtOAc and washed with water, brine, dried over MgSO4 filtered and evaporated to produce an oil. The oil was purified on a preparative TLC plate to produce the desired product (72%). 1H NMR (500 MHz, CDCl3): δ 2.40 (s, 3H), 3.99 (s, 3H), 4.55 (s, 2H), 6.84 (s, 1H), 6.92-6.93 (d, 1H), 7.16-7.19 (dd, 1H), 7.53-7.55 (d, 1H), 7.62-7.65 (m, 1H), 8.15-8.17 (d, 1H), 8.56-8.57 (d, 1H). MS (M+H, 313).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:60][C:61]([F:73])([F:72])[O:62][C:63]1[CH:71]=[CH:70][C:66]([C:67](Cl)=[O:68])=[CH:65][CH:64]=1>>[O:50]=[C:47]1[C:48]2[C:44](=[CH:43][CH:42]=[C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:67](=[O:68])[C:66]4[CH:70]=[CH:71][C:63]([O:62][C:61]([F:60])([F:72])[F:73])=[CH:64][CH:65]=4)=[CH:40][CH:39]=3)[CH:49]=2)[CH2:45][N:46]1[C:51]1([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCCC1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(OC(F)(F)F)cc5)cc4)cc3C2=O)CCCC1
Yield: 77 %

Procedure:
The compound of example 534 was prepared analogous to compound of example 97 by reaction of compound of example 527 with 4-trifluoromethoxy benzoyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCN(C(C)C)C(C)C.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](=[O:32])[C:29](Cl)=[O:30])=[CH:20]1>CN(C=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:29](=[O:30])[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][CH:20]=1)=[O:32])[CH3:2]
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: CCc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccccc1NC(=O)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a stirring solution of 2-ethyl-aniline (74 μL, 0.6 mmol) and DIEA (110 μL, 0.6 mmol) in DMF (1 mL) was added a solution of (1H-indol-3-yl)-oxo-acetyl chloride (62 mg, 0.3 mmol) in DMF (1 mL). The reaction was stirred at room temperature for 2 hours, then filtered and purified by HPLC (10-99% CH3CN/H2O) to yield the product N-(2-ethyl-phenyl)-2-(1H-indol-3-yl)-2-oxo-acetamide (34 mg, 39%). HPLC ret. time 3.50 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 10.14 (s, 1H), 8.79 (d, J=3.2 Hz, 1H), 8.30 (m, 1H), 7.57 (m, 2H), 7.33-7.21 (m, 5H), 2.67 (q, J=7.6 Hz, 2H), 1.17 (t, J=7.6 Hz, 3H); ESI-MS m/z 293.1 (MH+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[NH:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1>O1CCOCC1.C(O)(=O)C>[Br:1][C:11]1[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:14][C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1[nH]c(C)cc1-c1ccccc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c(C)c(Br)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
N-Bromo succinimide (1.40 g, 7.87 mmol) was added to a solution of ethyl 5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.5 g, 6.55 mmol) in a mixture of dioxane (10 mL) and acetic acid (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. The reaction mixture was warmed to room temperature and stirred for another 15 min. The mixture was quenched with 2N NaOH solution and the organic layer was separated, washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 4-bromo-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.68 g, 84%) as a solid.
Reaction SMILES: C[NH2:2].CCO.CO[C:8]([C:10]1[C:11]2[N:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:18]=2)[CH:13]=[CH:14][N:15]=1)=O>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:11]3[C:10]([CH2:8][NH2:2])=[N:15][CH:14]=[CH:13][N:12]3[CH:16]=2)=[CH:20][CH:21]=1
Reactant: CN
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Solvent: CCO
Product: NCc1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 100 °C
Yield: 91 %

Procedure:
In a sealed tube vessel was added 8M methylamine in EtOH (10 mL, 80 mmol) and 8-chloro-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (prepared from general procedure B using 3-chloropyrazin-2-ylamine and 2-bromo-1-(4-fluorophenyl)-ethanone; 2.30 g, 9.3 mmol). The mixture was heated at about 100° C. for about 1 h. The mixture was cooled to ambient temperature and the reaction mixture was partitioned between water and dichloromethane. The layers were separated. The organic layer was washed with brine, dried over Na2SO4, and filtered prior to concentrating under reduced pressure. The product was purified by silica gel chromatography using EtOAc/heptane (1:1) to give the title compound as a beige solid (2.05 g, 91%): LC/MS (Table 1, Method a) Rt=1.70 min; MS m/z: 243.3 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH2:4][CH2:3]1.C(#N)C.[CH3:25][CH2:26][CH2:27]CCCC>CN(C=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>[NH2:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[C:8]([CH2:27][CH:26]=[CH2:25])[CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH2:4][CH2:3]1
Reactant: CCCCCCC
Reactant: CCOC(=O)Cn1c2c(c3cccc(Br)c31)CC(N)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=CCc1cccc2c3c(n(CC(=O)OCC)c12)CCC(N)C3
Temperature: 25 °C

Procedure:
To a stirred and degassed solution of an appropriately protected ethyl (3-amino-8-bromo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 2c (0.2 mmol) and Pd(PPh3)4 (0.02 mmol, 0.1 eq.) in dry DMF (1.5 ml) is added under inert atmosphere the appropriate tetraC1-5-alkyltin or allyltrialkyltin, respectively (0.22 mmol, 1.1 eq.). The reaction mixture is allowed to stir overnight at 110° C. After cooling to rt, acetonitrile (1 ml) and heptane (1 ml) are added. The acetonitrile-DMF phase is washed three times with heptane. Water is then added and the resulting aq. phase is extracted twice with AcOEt. The combined org. phases are washed with brine and dried over Na2SO4. Evaporation of the solvent in vaccuo yields the protected ethyl (3-amino-8-C1-5-alkyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative or ethyl (3-amino-8-allyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1, respectively.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7][N:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:4].Br[CH2:18][CH2:19]Br>C(OCC)C.CS(C)=O>[CH:9](=[N:8][C:7]1([C:6]([O:5][CH2:3][CH3:4])=[O:16])[CH2:19][CH2:18]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CN=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C1(N=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
25.2 g (1.05 moles) of sodium hydride are added a little at a time under nitrogen to 100 g (0.523 mole) of N-benzylideneglycine ethyl ester and 45.1 ml (0.523 mole) of 1,2-dibromoethane in 500 ml of dry diethyl ether and 170 ml of dry dimethylsulfoxide, so that the well-stirred mixture remains at from 20° to 30° C. The mixture is stirred at room temperature overnight and filtered, and 1 l of water is added to the filtrate. The ethereal phase is separated off, washed with twice 200 ml of water, dried over sodium sulfate and evaporated under reduced pressure to give 80 g (70%) of ethyl N-benzylidene-1-aminocyclopropanecarboxylate as an oil.