Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:40])[C@H:10]([CH3:39])[CH2:11][C@H:12]([NH:26][C:27](=[O:38])[C:28](=[O:37])[NH:29][NH:30][C:31](=O)[C:32]([F:35])([F:34])[F:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([NH:26][C:27]([C:28]2[O:37][C:31]([C:32]([F:34])([F:35])[F:33])=[N:30][N:29]=2)=[O:38])[CH2:11][C@@H:10]([CH3:39])[C:9]([OH:8])=[O:40])=[CH:15][CH:16]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C(=O)NNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnc(C(F)(F)F)o1)C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-{2-oxo-2-[N′-(2,2,2-trifluoro-acetyl)-hydrazino]-acetylamino}-pentanoic acid benzyl ester (177 mg, 0.319 mmol) in THF (10 mL) at room temperature is added Burgess reagent (304 mg, 1.274 mmol). The reaction is carried out in a microwave at 130° C. for 30 minutes. The reaction is quenched by brine and is extracted with ethyl acetate. The combined organic layer is concentrated and purified by reverse phase HPLC [70% to 85% acetonitrile-H2O (containing 0.1% TFA)] to give the benzyl ester of the title compound. The obtained benzyl ester intermediate is dissolved in MeOH (4 mL) and is hydrogenated with 10% Pd/C at room temperature for 20 minutes. The reaction mixture is purified by reverse phase HPLC [45% to 70% acetonitrile-H2O (containing 0.1% TFA)] to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-[(5-trifluoromethyl-[1,3,4]oxadiazole-2-carbonyl)-amino]-pentanoic acid. HPLC Retention time 1.38 minutes (condition D); MS 448 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.3 Hz, 3H), 1.60-1.71 (m, 1H), 1.84-1.95 (m, 1H), 2.41-2.49 (m, 1H), 2.80-2.88 (m, J=13.9, 6.1 Hz, 1H), 2.92 (dd, J=13.6, 7.8 Hz, 1H), 4.21-4.34 (m, 1H), 7.27-7.37 (m, 3H), 7.44 (t, J=7.7 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.61-7.66 (m, 2H), 9.50 (d, J=8.8 Hz, 1H), 12.05 (br. s., 1H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]2[C:10]=1[F:23])=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([O-:30])=[O:25].[CH2:21]([O:20][C:18]([C:17]1[CH:16]=[N:15][N:12]2[CH:13]=[CH:14][C:9]([NH3+:8])=[C:10]([F:23])[C:11]=12)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cnn2ccc(NC(=O)OC(C)(C)C)c(F)c12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cnn2ccc([NH3+])c(F)c12
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of ethyl 5-((tert-butoxycarbonyl)amino)-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylate (7 g, 21 mmol) in DCM (60 mL), TFA (12 g, 108 mmol) was added at 0-5° C. drop wise over a period of 30 min, then stirred at room temperature for 2 hrs, reaction mass was concentrated at temperature below 40° C. under reduced pressure to afford the title compound (7 g) which was used in the next step without further purification, MS m/z 223.2 (M+) Step-4: Ethyl 5-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylate
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>>[Cl:19][CH2:20][CH2:21][CH2:22][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2cc(F)ccc2N1CCCCl
Yield: 104.6 %

Procedure:
7-Fluoro-4H-benzo[1,4]oxazin-3-one (81MF763) (0.263 g, 1.57 mmol), Cs2CO3 (0.769 g, 2.36 mmol) and 3-chloro-1-iodopropane (0.354 g, 1.73 mmol) were mixed according to GP5 giving the crude title compound (0.40 g); 1H NMR (CDCl3) d 7-01-6.91 (m, 1H), 6.79-6.73 (m, 2H), 4.60 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.4 Hz, 2H, 2.18-2.11 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]([C:8](=O)[CH3:9])[C:6]#[N:7].O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[C:8]([CH3:9])=[N:17][NH:18][C:6]=1[NH2:7]
Reactant: CC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To a solution of 2-(2,3-dichlorobenzyl)-3-oxobutanenitrile (2.19, 9.05 mmol) in ethanol (400 mL) was added hydrazine hydrate (0.452 g, 9.05 mmol) and the resulting solution was stirred under reflux for 16 h. Then the mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate=1/1 then DCM:methanol=40:1) to provide the titled compound (1.21 g, 52%) as a yellow solid; LC/MS: MS (ES+) m/e 256 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.13 (s, 3H), 3.77 (s, 2H), 6.97 (dd, J=1.2, 7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 7.33 (dd, J=1.2, 7.8 Hz, 1H)
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].[P:10](Cl)(Cl)(=[O:18])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1C=CN=C1.[C:27]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:28][CH2:29][NH:30][C:31](=[O:39])[C@@H:32]([C:34]([CH2:37][OH:38])([CH3:36])[CH3:35])[OH:33]>C(Cl)Cl.CO>[CH2:2]([O:4][C:5](=[O:9])[C@@H:6]([NH:7][P:10]([O:38][CH2:37][C:34]([CH3:36])([CH3:35])[C@@H:32]([OH:33])[C:31]([NH:30][CH2:29][CH2:28][C:27]([O:41][CH2:42][CH3:43])=[O:40])=[O:39])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[CH3:8])[CH3:3]
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: CCOC(=O)[C@H](C)N
Reactant: CCOC(=O)CCNC(=O)[C@H](O)C(C)(C)CO
Agent: Cl
Agent: Cn1ccnc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(N[C@@H](C)C(=O)OCC)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
L-Alanine ethyl ester hydrochloride (0.50 g, 3.25 mmol) was suspended in 10 mL of CH2Cl2 and treated with phenyl phosphorodichloridate (0.50 mL, 3.35 mmol) at −10° C. and under an atmosphere of nitrogen. The well-stirred mixture was then treated dropwise with N-methylimidazole (1.0 mL, 12.5 mmol). After 1 hr. and still at −10° C., ethyl pantothenate (0.70 g, 2.8 mmol) in 3 mL of CH2Cl2 was added slowly. This mixture was allowed to warm to room temperature, and after 3 hrs, 2 mL of methanol was added. Extraction was performed sequentially with 1 M HCl, water, 5% NaHCO3, and brine. The organic phase was dried (Na2SO4), and the solvent was evaporated affording 1.11 g of a clear, colorless syrup. This material was purified by flash column chromatography using 30 g of silica gel and eluting with 1:1 EtOAc/hexanes containing 5% EtOH. The process was repeated until 1.1 g of phosphoramidate was obtained. HPLC showed the product, as a 1:1 mixture of disastereomers, having a purity of 97%. 1H NMR (300 MHz, CDCl3): δ 1.08 (s, 3H, CH3), 1.21 (d, 3H, J=2.7 Hz, CH3), 1.27 (m, 6H, CH3), 1.35 (t, 3H, J=6.9 Hz, CH3), 2.53 (q, 2H, J=4.2 Hz, CH2), 3.50 (m, 2H, CH2), 3.60 (m, 1H, CH), 3.78 (d, J=7.5 Hz, CH), 3.9 (m, 2H, CH2), 4.10 (m, 6H, CH2), 4.79 (t, 1H, J=6.5 Hz, CH), 7.15 and 7.40 (2Ms, 5H, Ph). Expected Mol. Wt. 502.21, Observed Mol. Wt. 503.09 (M+H+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](COCC[Si](C)(C)C)C=1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39](Br)=[CH:38][C:37]=1[C:43]([N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)=[O:44].C([O-])(O)=O.[Na+].C(#[N:58])C>>[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:58][NH:11][C:12]3=[N:13][CH:14]=2)=[CH:38][C:37]=1[C:43]([N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)=[O:44]
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC#N
Reactant: Nc1ccc(Br)cc1C(=O)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(N)c(C(=O)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 5 mL Personal Chemistry microwave reaction vial were added 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (0.0498 g, 0.103 mmol), (2-Amino-5-bromo-phenyl)-morpholin-4-yl-methanone (0.0378 g, 0.132 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (13.4 mg, 0.017 mmol), acetonitrile (1 mL) and saturated aqueous NaHCO3 (1 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90° C. for 5 min. The layers were separated, and the aqueous phase was extracted 3× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in 5 mL of a solution consisting of 1 part HClO4 (70%, ACS) and 20 parts glacial acetic acid, and the solution was stirred at rt for 8 h. The reaction mixture was concentrated under vacuum, and neutralized to pH 7 with saturated NaHCO3 followed by solid NaHCO3. The quenched reaction mixture was partitioned between EtOAc and water, the layers were separated, and the aqueous phase was extracted 2× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by mass-triggered LC (positive mode, ESI) through a C-18 reverse-phase column (Thomson Instrument Co. ODS-A 100 A, 5μ, 50×21.3 mm, eluting at 20 mL/min with acetonitrile (containing 0.1% formic acid) and water (containing 0.1% formic acid) in a 5-95% gradient afforded the title compound, which upon lysophilization appeared as a brown viscous oil (12.9 mg, 29%). 1H-NMR (500 MHz, d6-DMSO) δ 13.71 (br. s, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.49 (dd, J=2.5, 8.0 Hz, 1H), 7.45 (m, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.08 (t, J=8.5 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 5.37 (s, 2H), 3.83 (s, 3H), 3.60 (m, 4H), 3.49 (m, 4H); MS: m/z 430.1 [MH+].
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cn1
Yield: 61.1 %

Procedure:
3-tert-Butyl-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-amine (736 mg, 2.98 mmol) was treated with phenyl chloroformate (1.50 mL, 12.0 mmol) according to the procedure in Example 118A to afford phenyl 3-tert-butyl-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-ylcarbamate (665 mg, 1.82 mmol, 61%). 1H NMR (300 MHz, DMSO-d6) δ 10.07 (br s, 1H), 8.31 (s, 1H), 7.83 (d, 1H), 7.39 (t, 2H), 7.23 (t, 1H), 7.08 (br s, 2H), 6.98 (d, 1H), 6.36 (s, 1H), 3.92 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 367 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:13][CH2:12][CH:11]2[CH2:14][CH2:15][CH2:16][N:9]3[C:10]2=[C:2]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13.ClC1C(=O)C(C#N)=C(C#N)C(=[O:25])C=1Cl>O1CCCC1.O>[C:1]1(=[O:25])[CH2:13][CH2:12][CH:11]2[CH2:14][CH2:15][CH2:16][N:9]3[C:10]2=[C:2]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13
Reactant: c1ccc2c(c1)c1c3n2CCCC3CCC1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC2CCCn3c2c1c1ccccc13
Temperature: 0 °C

Procedure:
7.2 g (0.034 mol) of 2,3,3a,4,5,6-hexahydro-1H-pyrido[3,2,1-jk]carbazole prepared according to A. S. Baily et al. J. C. S. Perkin I (1980) 97, were dissolved in 300 ml of tetrahydrofuran. The mixture was diluted with 30 ml of water and cooled to 0° C. A solution of 17.0 g (0.075 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 150 ml of tetrahydrofuran was added dropwise in 10 minutes while stirring thoroughly at a reaction temperature between 0° and 5° C. The reaction mixture was stirred for 1 hour and evaporated in vacuum. The residue was extracted with methylene chloride. The methylene chloride solution was washed with 200 ml of 0.5N sodium hydroxide solution and evaporated in vacuum. The residue was chromatographed over 500 g of silicagel using ethyl acetate as an eluent. After evaporating the good fraction, the desired ketone was obtained in a yield of 4.6 g (60%) having a melting-point of 172°-173° C.
Reaction SMILES: [C:1](=[O:3])=O.[CH2:4]=[C:5]([CH3:7])[CH3:6].[CH2:8]=[O:9].S([O-])([O-])=O.[Na+].[Na+]>C=O.P([O-])([O-])(O)=O.[Na+].[Na+].CO.C(O)(C)(C)C>[CH3:6][C:5](=[CH2:4])[CH2:7][CH2:1][OH:3].[CH3:6][C:5]([CH3:7])=[CH:4][CH2:8][OH:9]
Reactant: O=C=O
Reactant: C=C(C)C
Reactant: C=O
Agent: O=P([O-])([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)(C)O
Product: C=C(C)CCO
Product: CC(C)=CCO
Temperature: 200 °C
Reaction time: 4 h

Procedure:
In a stainless steel autoclave having an inner volume of 300 ml, 9.0 g of paraformaldehyde of 95% purity, 0.22 g of sodium hydrogenphosphate as catalyst, and 60 ml of t-butanol were placed and the autoclave was closed. While cooling the autoclave with a dry ice and methanol mixture, the air in the autoclave was replaced by nitrogen and then 150 ml of isobutene was added thereto. Then the autoclave was brought to room temperature and no leak was found. Then the mixture was reacted with stirring at 200° C. for 4 hours. After the reaction, the autoclave was cooled and the contents were taken off. The reaction product was pale yellow and no substance having high boiling point was found. The reaction product was analyzed quantitatively by gas chromatography. Conversion of paraformaldehyde was determined by the sodium sulfite method. Conversion of paraformaldehyde was 98.9 mole%, and there were obtained 85.0 mole% of 3-methyl-3-butene-1-ol and 5.9 mole% of 3-methyl-2-butene-1-ol based on the paraform-aldehyde reacted. Total selectivities for the unsaturated alcohols were 90.9 mole% and no 4,4-dimethylmetadioxane was produced.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:27]1[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@@H:29]2[CH2:30][CH2:31][C@@H:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@@H]1CC[C@@H](c2ccccn2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1COc2c(N[C@@H]3CC[C@@H](c4ccccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 100 °C
Reaction time: 7 h
Yield: 15.3 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (1.40 g, 5.05 mmol), (1R,3R)-3-(2-pyridyl)cyclopentylamine (985 mg, 6.07 mmol) and triethylamine (1.40 mL, 10.0 mmol) in anhydrous DMSO (8 mL) was stirred at 100° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[(1R,3R)-3-(2-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (325 mg, 15%) as a yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1c(C(=O)N2CCCCC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCCCC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccncc3)c21
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (60 mg, 0.3 mmol), 3-methyl-4-(piperidine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (75 mg, 0.34 mmol) and piperidine (0.14 mL) in ethanol (2 mL) was stirred at 100° C. overnight. The reaction was column chromatographed (2-3% methanol in dichloromethane) to give 20 mg (17%) of the title compound as a yellow orange solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[C@@H:13](Br)[C@H:12]([OH:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=2)[O:5]1>CS(C)=O>[CH3:3][C:4]1([CH3:18])[CH:13]2[O:15][CH:12]2[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=2)[O:5]1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reaction time: 1 h

Procedure:
0.4 g of a 60% dispersion of NaH in oil is added with stirring to a solution of 2.82 g of trans-2,2-dimethyl-3-bromo-6-cyanochroman-4-ol in 15 ml of DMSO. The mixture is stirred for 1 hour, 2,2-dimethyl-3,4-epoxy-6-cyanochroman being formed as an intermediate. 1.43 g of 1H-2-pyridone and a further 0.5 g of the NaH dispersion are added and the mixture is stirred for 16 hours at 20°. Working up analogously to Example 1 gives "A" (m.p. 146-148°) and "B" (m.p. 244°).
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[C:56]([O:59]C1C=CC=CC=1C(Cl)=O)(=[O:58])[CH3:57].C(N(CC)CC)C>O1CCCC1>[C:56]([O:59][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])(=[O:58])[CH3:57]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3OC(C)=O)nn2)cc(OC)c1OC
Yield: 95 %

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (95 mg, 0.31 mmol), 2-(chlorocarbonyl)phenyl acetate (65 mg, 0.33 mmol), and triethylamine (0.050 mL, 0.36 mmol) in tetrahydrofuran (2 mL) gave 2-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}phenyl acetate (138 mg, 95%) as an off yellow solid. MS m/z 467 (M+1).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[C:44]3[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=3)[CH2:38][N:37]([CH3:47])[CH2:36]2)[CH:30]=1)(=[O:28])=[O:27]>>[Cl:45][C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([Cl:46])[CH:41]=1)[CH2:38][N:37]([CH3:47])[CH2:36][CH:35]2[C:31]1[CH:30]=[C:29]([S:26]([NH:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]4[C:44]5[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=5)[CH2:38][N:37]([CH3:47])[CH2:36]4)[CH:30]=3)(=[O:28])=[O:27])=[O:12])=[CH:10][CH:9]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)c3ccc(C(=O)NCCOCCOCCOCCNS(=O)(=O)c4cccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)c4)cc3)c2)C1
Yield: 58.7 %

Procedure:
Compound 216 was prepared following the procedure outlined in Example 215 using terephthalic acid (10.7 mg, 0.0646 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 100 mg, 0.129 mmol). Purification by preparative HPLC gave the title compound (46.3 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.87 (m, 6H), 7.73 (s, 2H), 7.59 (t, 2H), 7.52-7.49 (m, 4H), 6.80 (s, 2H), 4.77-4.69 (m, 4H), 4.49 (d, 2H), 3.587 (qs, 2H), 3.67-3.54 (m, 27H), 3.45 (t, 5H), 3.40 (t, 5H), 3.13 (s, 7H), 2.99 (t, 4H). MS (m/z): 1224.34 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=2.C(O[C:19](=[O:30])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)(C)(C)C.[Cl:31][C:32]1[C:42](C(O)=O)=[CH:41][C:35]2[NH:36][C:37](=[O:40])[CH2:38][S:39][C:34]=2[CH:33]=1>>[C:12]([C:8]1[CH:9]=[C:10]2[C:5]([N:4]=[CH:3][C:2]([O:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:42]4[C:32]([Cl:31])=[CH:33][C:34]5[S:39][CH2:38][C:37](=[O:40])[NH:36][C:35]=5[CH:41]=4)=[O:30])[CH2:26][CH2:25]3)=[N:11]2)=[CH:6][CH:7]=1)#[N:13]
Reactant: N#Cc1ccc2ncc(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)cc2N1
Product: N#Cc1ccc2ncc(OCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCC(=O)N5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow lyophilizated powder following Scheme 1 and in analogy to Example 1 using 3-chloro-quinoxaline-6-carbonitrile, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2F)[N:6]=1)=[O:4].[Br:24]N1C(=O)CCC1=O.[FH:32].[FH:33].F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]([F:32])[CH2:12][Br:24])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:33])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: F
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1C(F)CBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylic acid methyl ester (0.611 g, 1.809 mmol) and N-bromosuccinimide (0.386 g, 2.171 mmol) were dissolved in dichloromethane (10 ml) and the reaction mixture was cooled to 0° C. Triethylamine trihydrofluoride (0.884 mL, 5.43 mmol) was then added dropwise and the reaction mixture was allowed to warm to ambient temperature and stirred overnight. Water and additional dichloromethane were added. Sodium bicarbonate (0.760 g, 9.05 mmol) was added in several portions until no further gas evolution was noted. The organic phase was dried and concentrated under vacuum. The product was purified by flash chromatography on silica gel twice (first with dichloromethane/ethyl acetate gradient followed by hexane/ethyl acetate gradient) to provide the title compound (352 mg, 0.806 mmol, 44.6% yield) as a white solid, mp 144-146° C.: 1H NMR (CDCl3) δ 7.67 (dd, 1H), 7.23 (dd, 1H), 6.32 (ddd, 1H), 5.77 (br s, 2H), 4.01 (s, 3H), 4.0 (d, 3H), 3.77-3.94 (m, 2H).