Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:15]=[C:14]([CH3:16])[S:13][CH:12]=1)[OH:4].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:15]=[C:14]([CH3:16])[S:13][CH:12]=2)[C:2]([F:1])([F:17])[F:18])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(-c2ccccc2C(O)C(F)(F)F)cs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cs1
Temperature: 110 °C
Yield: 68.2 %

Procedure:
A mixture of 2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethanol (100 mg, 0.37 mmol), 2-amino-4,6-dichloro-pyrimidine (54 mg, 0.33 mmol), cesium carbonate (481 mg, 1.48 mmol) and 1,4-dioxane (2 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 90 mg of 4-chloro-6-{2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine, yield: 68%
Reaction SMILES: C(OC([O:6][C:7]1[C:8]2[N:9]([CH:28]=[CH:29][N:30]=2)[C:10]2[C:19](C([O-])=O)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:11]=2[N:12]=1)=O)C.[ClH:31].C(OCC)(=O)C>O1CCCC1.O>[ClH:31].[CH:28]1[N:9]2[C:10]3[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:11]=3[NH:12][C:7](=[O:6])[C:8]2=[N:30][CH:29]=1
Reactant: CCOC(=O)Oc1nc2c(n3ccnc13)C(C(=O)[O-])(C(=O)OCC)c1ccccc1-2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 8 h

Procedure:
To a solution of 0.22 g of ethyl 4-ethoxycarbonyloxy-10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-10,10-dicarboxylate in 20 ml of tetrahydrofuran are added 5.5 ml of 1N hydrochloric acid at a temperature in the region of 20° C. After reacting overnight at the same temperature, the tetrahydrofuran is evaporated off under reduced pressure (15 mmHg; 2 kPa) and the aqueous solution thus obtained is diluted with 5 ml of distilled water. The addition of 10 ml of ethyl acetate causes formation of a cream-coloured precipitate which is filtered off, washed and dried to give 0.15 g of ethyl 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one-10-carboxylate hydrochloride in the form of a cream-coloured solid (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 1.23 (t, J=7.5 Hz, 3H: --CH3 ethyl); from 4.00 to 4.40 (mt, 2H: --OCH2 -ethyl); 5.41 (s, 1H: --CH-- 10); 7.43 and 7.51 (2 broad t, J=8 Hz, 1H each: --H 7 and --H 8); 7.75 and 7.97 (2 broad d, J=8 Hz, 1H each: --H 6 and --H 9); 7.82 and 8.14 (2s, 1H each: --H of the imidazole); 12.95 (mult., 1H: --CONH--)).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1.Cl[C:18]1[N:19]([CH3:31])[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[N:23]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:31][N:19]1[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[N:23]=[C:18]1[O:3][CH:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(OC2CCCNC2)nc(-c2ccncn2)cc1=O
Reaction time: 1 h

Procedure:
To a mixture of sodium hydride (60 wt % in mineral oil, 0.24 g, 6.0 mmol) in N,N-dimethylformamide (15 ml) at room temperature under nitrogen atmosphere was added a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (1.0 g, 5.0 mmol) in N,N-dimethylformamide (5 ml) dropwise. After the mixture was stirred for one hour, 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (1.1 g, 5.0 mmol) was added to the mixture. The resulting mixture was stirred overnight and poured into water. Extractive workup was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. To the residue was added 4N hydrogen chloride in ethyl acetate (10 ml) and the resulting slurry was stirred at room temperature for 2 hours. After concentration under reduced pressure, the residue was dissolved in water. The aqueous solution was washed with ethyl acetate and basified with potassium carbonate. Extraction with chloroform was performed three times and the organic layer was dried over anhydrous sodium sulfate. After concentration, analytically pure 1-methyl-2-(piperidine-3-yloxy)-1H-[4,4′]bipyrimidinyl-6-one was isolated as a white solid (0.66 g, 2.3 mmol, 46%). This compound was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[Cl:17]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([Cl:17])=[C:9]([CH3:11])[N:8]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[C:6]=2[N:7]=1
Reactant: Cc1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1c(Cl)c2cnc(Cl)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
To a solution of 2-Chloro-7-cyclopentyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (164 mg, 0.70 mmol) in dichloromethane (3 mL) is added N-chlorosuccinimide (0.4M in DCM, 1.1 eq) over 1 h. The reaction mixture is allowed to stir for 3 days at room temperature. The reaction mixture is diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate followed by brine. The organic phase is concentrated and the crude product is purified by normal phase chromatography (SiO2, EtOAc/heptane) to obtain 2,5-Dichloro-7-cyclopentyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (158 mg, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH:27]=O)=[CH:21]2)[CH3:13].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:27][C:22]1[NH:23][C:24]2[C:20]([CH:21]=1)=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:14]([CH2:12][CH3:13])[CH2:29][CH3:30])=[CH:26][CH:25]=2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccc(Br)cc43)cc2c1
Temperature: 100 °C
Yield: 66 %

Procedure:
A mixture of 5-bromo-2-oxindole (41 mg, 0.2 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 60 mg (66%) of the title compound.
Reaction SMILES: C(C1[CH:4]=[C:5]2[C:13](=CC=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][C@@H:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:7][C:6]2=1)#N.[CH3:30][Mg]Br.[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[C:37]([C:36]1[CH:35]=[C:34]2[C:13](=[CH:5][CH:4]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][C@@H:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:7][C:6]2=1)(=[O:33])[CH3:30]
Reactant: C[Mg]Br
Reactant: C1CCOC1
Reactant: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Product: CC(=O)c1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C(C)C)C1
Yield: 74 %

Procedure:
Treat (R)-N-[6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide (Example 123) (2.07 g, 5.32 mmol) with methyl magnesium bromide (9 mL) in refluxing tetrahydrofuran for 18 h. Quench with MeOH, filter to remove the solids, and concentrate in vacuo. Treat the residue with 1N HCl/THF and reflux for 2 h. Add ethyl acetate, filter to remove insoluable precipitate, and concentrate the filtrate in vacuo to give 2.7 g (74%) of a yellow solid. MS (ES): m/z 407 (M+1); HPLC: Rt=2.3 min (97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:25]([O:27]CC2C=CC=CC=2)=[O:26])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].C(O)(=O)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]([C:11]1([C:25]([OH:27])=[O:26])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:22])[Cl:23])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCCC(C(=O)OCc2ccccc2)(C(=O)OCc2ccccc2)C1
Agent: [K]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1CCCC(C(=O)O)(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3,3-dibenzyl ester (5.5 g 15 mmol) in N,N-dimethylformamide (200 mL) cooled with a water/ice bath, is added potassium hydroxyde (0.9 g 85% 14 mmol) dissolved in water (40 mL). The mixture is stirred with cooling for 2 h, allowed to warm to room temperature, acidified with acetic acid (1.05 ew) and concentrated under reduced pressure. Addition of water cristallizes the crude which is filtered, dissolved in ethyl acetate, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. Cristallisation with heptane affords piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3-benzyl ester.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([O:35][CH3:36])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[N:6]3[CH:7]=[C:8]([NH:11][CH:12]4[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:23]=[C:22]([O:35][CH3:36])[N:21]=1
Reactant: OC1CCCC(Nc2ccc3ncc(Br)n3c2)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnc3ccc(NC4CCCC(O)C4)cn23)cc(Cl)n1
Temperature: 95 °C

Procedure:
To a solution of 3-trans-RS/RS(3-bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol [intermediate J step 2] (1 eq, 10.1 mmol, 3.4 g), 2-Chloro-6-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.05 eq, 10.1 mmol, 2.9 g), Na2CO3 (2 eq, 19 mmol, 2 g) in dioxane (45 ml) and water (13.5 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.96 mmol, 224 mg). The reaction mixture is heated at 95° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+=343/345.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].CO[C:21](OC)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:22][C:21]1([CH3:23])[O:9][CH:8]2[CH:10]([C@@H:12]([CH2:13][OH:14])[O:15][C@H:7]2[N:6]2[C:5](=[O:17])[NH:4][C:3](=[O:18])[C:2]([F:1])=[CH:16]2)[O:11]1
Reactant: COC(C)(C)OC
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OC2C(O1)[C@@H](CO)O[C@H]2n1cc(F)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 84 %

Procedure:
In 750 ml of acetone were added 15 g of 5-fluorouridine, 7.5 ml of 2,2-dimethoxypropane and 1.1 g of p-toluenesulfonic acid monohydrate, and the mixture was reacted at room temperature for 4.5 hours under stirring. After allowed to stand overnight at room temperature, 5 g of sodium hydrogen carbonate was added to the reaction mixture and the mixture was stirred at room temperature for 2.5 hours. After insolubles were filtered off, the filtrate was condensed under reduced pressure, and the obtained crystals were recrystallized from ethanol to give 15.7 g (Yield: 84%) of the title compound as colorless needle crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].C(O)(=O)C.N1CCCCC1>ClCCl>[C:16]([C:15]([C:14](=[O:19])[CH3:13])=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])(=[O:18])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: COc1cc(C#N)ccc1C=O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1cc(C#N)ccc1C=C(C(C)=O)C(C)=O

Procedure:
21 g (130 mmol) of 4-formyl-3-methoxybenzonitrile, 14.7 ml (143 mmol) of 2,4-pentanedione, 11.2 ml (195 mmol) of acetic acid and 2.6 ml (26 mmol) of piperidine in 400 ml of dry dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from diethyl ether. 23.2 g (92% of theory) of the title compound are obtained as a pale brown solid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH2:7][C@@H:6]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:5]2)[CH2:3][CH2:2]1.C1([O:23][C:24](=O)[NH:25][C:26]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[O:28][N:27]=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1>[NH3:4].[C:31]([C:29]1[O:28][N:27]=[C:26]([NH:25][C:24]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][C@@H:6]3[CH2:7][CH2:8][CH2:9][N:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:5]3)[CH2:12][CH2:13]2)=[O:23])[CH:30]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: C1C[C@@H](CN2CCNCC2)CN(C2CC2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)N2CCN(C[C@@H]3CCCN(C4CC4)C3)CC2)no1
Product: N
Temperature: 60 °C
Yield: 105.1 %

Procedure:
A mixture of 1-{[(3S)-1-cyclopropylpiperidin-3-yl]methyl}piperazine (60 mg), phenyl(5-tert-butylisoxazol-3-yl)carbamate (84 mg) and triethylamine (54 mg) in tetrahydrofuran (4 mL) was heated to 60° C. in the microwave for 1 hour. The solution was concentrated at reduced pressure and then purified by reverse phase prep HPLC eluting with a mixture of 5-95% acetonitrile in water and then SCX-2 column eluting with methanol then 7M NH3 in methanol to give the title compound as a white solid (55 mg, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].C(O[C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1)C.[CH2:28]1COC[CH2:29]1>>[Br:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5]([Cl:14])=[C:6]([C:7]([C:20]2[CH:21]=[CH:22][C:23]([CH2:28][CH3:29])=[CH:24][CH:25]=2)=[O:8])[CH:13]=1
Reactant: CCOc1ccc([Mg]Br)cc1
Reactant: COc1cc(Br)cc(C(=O)N(C)OC)c1Cl
Reactant: C1CCOC1
Product: CCc1ccc(C(=O)c2cc(Br)cc(OC)c2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of compound 60 (3.45 g, 11.2 mmol) in THF (44 mL) was added dropwise 4-ethoxyphenyl magnesium bromide (0.5 M in THF, 44.8 mL, 22.4 mmol) at 0° C. under an atmosphere of nitrogen. After being stirred for 15 hours at room temperature, the mixture was quenched with 1 N HCl (10 mL). The mixture was extracted with EtOAc (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the product 61 (3.92 g, 99%) as a white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@@H:13]([OH:26])[CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[CH2:8][CH2:7]1)=[O:5])C.O.CO.[OH-].[Li+:31]>O1CCCC1>[OH:26][C@@H:13]([CH2:14][O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2)[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([C:4]([O-:5])=[O:3])[CH2:7][CH2:8]1.[Li+:31]
Reactant: CCOC(=O)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
(R)-1-[2-Hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylic acid ethyl ester (31) (1.15 g; 3.21 mmol) is dissolved in 21 mL of a 40:40:20 mixture of tetrahydrofuran:water:methanol. Lithium hydroxide (81 mg; 3.37 mmol) is added and the mixture stirred at ambient temperature. After 4.5 hours, the mixture is concentrated in vacuo at 40° C. Further drying on the vacuum pump affords the desired product (32) as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[CH2:3][CH2:4][OH:5].ClCCl.C(N(CC)CC)C.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>O>[CH3:28][S:25]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCO)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CCOS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
To a mixture of 2-[methyl(3-nitrophenyl)amino]ethanol (780 mg) and dichloromethane (20 mL), triethylamine (0.66 mL) and mesyl chloride (0.37 mL) were added sequentially under ice cooling and stirred for 3 hours. Water was added to the reaction liquid, and the organic layer was separated and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give 2-[methyl(3-nitrophenyl)amino]ethyl methanesulfonate (1.0 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=[O:12])[CH3:11])[C:7](=[O:9])[CH3:8])[CH3:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(O)(=O)C>N12CCCN=C1CCCCC2.C(OCC)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([C:7](=[O:9])[CH3:8])([C:10](=[O:12])[CH3:11])[CH2:16][CH2:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)CCC(CC(=O)OCC)(C(C)=O)C(C)=O
Reaction time: 24 h
Yield: 81.2 %

Procedure:
37 g of 3-acetyl-4-oxo-pentanoic acid ethyl ester, synthesized according to the procedure given in Example 15, and 0.3 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were mixed, and 30 g of ethyl acrylate was added dropwise over 30 minutes. After stirring for 24 hours, the base was neutralized by adding acetic acid. 80 ml of diethyl ether was added, and the mixture was extracted with 60 ml of an aqueous sodium carbonate solution and 150 ml of water. Fractional distillation of the water-free organic layer yielded 46.2 g of 3,3-diacetyl-hexanedioic acid diethyl ester (boiling point: 150° C./0.03 mbar; purity: >99%; colorless).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of 1-(3-chlorophenyl)piperazine hydrochloride (12 g, 0.051 mol) in anhydrous toluene (250 ml) was added triethylamine (TEA) (15.6 ml, 0.112 mol) and ethyl 6-bromohexanoate (13.6 g, 0.061 mol) and the mixture heated at reflux for 4 hours. The mixture was then cooled to room temperature, washed with water (2×100 ml), brine (100 ml), dried over Na2SO4, filtered and concentrated to dryness. The residue obtained was purified by flash chromatography on silica gel using ethyl acetate/hexane (1/1) to give ethyl 6-[N′-(3-chlorophenyl)-N-piperazinyl]hexanoate (10.3 g) as a clear oil.
Reaction SMILES: [NH2:1][NH2:2].C(O)(=O)C.[Cl:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]([C:18](=O)[CH3:19])[C:16]#[N:17])=[C:10]([CH3:21])[CH:9]=1>C1(C)C=CC=CC=1>[NH2:17][C:16]1[NH:2][N:1]=[C:18]([CH3:19])[C:15]=1[C:11]1[C:12]([CH3:14])=[CH:13][C:8]([Cl:7])=[CH:9][C:10]=1[CH3:21]
Reactant: NN
Reactant: CC(=O)C(C#N)c1c(C)cc(Cl)cc1C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc(C)c1-c1c(C)n[nH]c1N
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
Dissolve anhydrous hydrazine (0.91 g, 0.90 mL) in 20 mL toluene. Add glacial acetic acid (2.25 mL) and allow to stand at ambient temperature for 10 min until solution becomes cloudy white. Add a solution of 2-(4-chloro-2,6-dimethylphenyl)-3-oxobutanenitrile in 10 toluene, rinsing out the ketonitrile flask with an additional 5 mL toluene. Heat to reflux under N2 (130° C.) with Dean-Stark trap attached. Water will begin to accumulate after 10 min or so. After 2 h, evaporate down and partition between 1.0 N NaOH (100 mL) and EtOAc (100 mL). Extract aqueous layer with EtOAc (2×100 mL), then pool the organic layers and dry over Na2SO4. Filter and evaporate to yellow oil (1.75 g). Use without further purification. LCMS=236.5 (MH+); 234.5 (M−).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=2)=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[C:29]([NH:32][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:30][N:31]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(-c2cc(N)[nH]n2)cc1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)cc1

Procedure:
The named compound is prepared by substituting 5-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2392 gms. of 5-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.O.[NH3+]N>O1CCCC1.[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:16]2[CH:15]=[CH:14][C:13]([S:10]([NH:9][C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=3)(=[O:12])=[O:11])=[CH:18][CH:17]=2)=[CH:22][CH:23]=1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NCc3ccc([N+](=O)[O-])cc3)cc2)n1
Agent: [Pd]
Agent: N[NH3+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NCc3ccc(N)cc3)cc2)n1
Reaction time: 8 h
Yield: 59 %

Procedure:
18 mg (0.04 mmol) of N-(4,6-dimethylpyrimidin-2-yl)-4-(4-nitrobenzylamino)-benzenesulfonamide was dissolved in 1 ml of tetrahydrofurane. Hydrazinium hydrate (50 μl, 1.5 mmol) and catalytic amount of palladium on charcoal were added to the reaction mixture. Solution was stirred overnight. The reaction mixture was evaporated to dryness and purified on silica using gradient elution (chloroform to 4% methanol in chloroform) to obtain with a yield of 59%. MS (ESI+): m/z 406 (M+H)+, 384 (M+H)+.