Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[C:12](=[O:18])[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:3]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[C:12](=[O:18])[C:13](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC2CCC1N2Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CC2CCC1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.9 %

Procedure:
A 5N sodium hydroxide solution (1.62 mL, 0.5 equiv.) was added to (±)-8-benzyl-8-aza-bicyclo[3.2.1]octan-2-one (3.49 g, 16.2 mmol), followed by a solution of benzaldehyde (2.59 mL, 2.69 g, 16.2 mmol) in ethanol (160 mL). The solution was stirred at ambient temperature for 4.5 h. The solution was concentrated under reduced pressure, and the residue was taken up in dichloromethane (160 mL). The mixture was washed with water (160 mL) and brine (160 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give crude product (4.96 g, theoretical yield 4.92 g) as an orange oil.
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:35][CH2:34][C:29]4([CH2:32][CH:31]([OH:33])[CH2:30]4)[CH2:28][CH2:27]3)=[N:24][CH:25]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:11][S:8]([O:33][CH:31]1[CH2:30][C:29]2([CH2:34][CH2:35][N:26]([C:23]3[CH:22]=[CH:21][C:20]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)=[CH:25][N:24]=3)[CH2:27][CH2:28]2)[CH2:32]1)(=[O:10])=[O:9]
Reactant: OC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Yield: 99.7 %

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.2.). 3.25 mL (23.34 mmol) of triethylamine and then 0.91 mL (11.67 mmol) of mesyl chloride are added to a solution of 2.43 g (7.78 mmol) of 7-[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]nonan-2-ol, obtained in step 10.2., in 25 mL of dichloromethane. 3.03 g of product are obtained in the form of a yellow oil, which is used without further purification in the following step.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[C:9]1[C:8]2[C:13](=[CH:14][C:15]([Cl:16])=[C:6]([NH:5][CH2:4][C:3]3[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:2]=3[CH3:1])[CH:7]=2)[N:12]=[C:11]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:10]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1cc2c(N(C)C)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C23H23ClN6O2, 450.9
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]([NH2:11])=[O:10])=[N:2]1.[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([N:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]([NH2:11])=[O:10])=[N:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:14]([N:2]1[CH:3]([C:9]([NH2:11])=[O:10])[C:4]2[CH2:8][CH2:7][CH2:6][C:5]=2[NH:1]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)c1n[nH]c2c1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)C1C2=C(CCC2)NN1Cc1ccccc1
Product: NC(=O)c1nn(Cc2ccccc2)c2c1CCC2
Reaction time: 16 h
Yield: 196.4 %

Procedure:
To a solution of 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid amide (41.5 g, 275 mmol) in THF (460 mL) at rt was added a solution of NaOH (5N aq., 110 mL, 0.54 mol). After stirring for 5 min benzyl bromide (49.2 g, 0.29 mol) was added and the reaction was stirred for 16 h. The volatiles were removed in vacuo and the resulting solid was washed with H2O (3×250 mL). Further concentration gave regioisomers of 1-benzyl-1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid amide and 2-benzyl-1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid amide (65.3 g, 270 mmol, 98% yield) as a 20:1 mixture and was used without separation).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[N:19]=1>>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[N:19]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: Clc1cccc(Cl)n1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)NC1CCN(c2cccc(Cl)n2)CC1
Reaction time: 40 h
Yield: 78.6 %

Procedure:
A suspension of 175.5 g of 4-acetamidopiperidine, 269.7 g of potassium carbonate and 182.5 g of 2.6-dichloropyridine in 1600 ml of n.penytylic alcohol is heated at reflux with stirring for 40 hours. The reaction mixture is cooled, the solvent is removed under reduced pressure and the residue is taken up with 100 mlof water. The solid product is extracted with 2000 ml of methylene chloride, the organic phase is washed with water, it is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is taken up with 1200 ml of diisopropylic ether, stirred for 30 minutes, filtered and washed with diisopropylic ether. 246 g of 4-acetamido-1-(6-chloro-2-pyridyl)piperidine are obtained; m.p. 153° to 155° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2ccc3ccc(Br)cc32)cc1
Reaction time: 0.5 h

Procedure:
A solution of 6-bromoindole (J. Org. Chem. 1986, 51, 5106) (3.00 g, 15.3 mmol) in DMF (65 mL) was treated with NaH (734 mg of a 60% suspension in mineral oil, 18.4 mmol). After 30 min, 4-fluorobenzyl bromide (1.90 mL, 15.3 mmol) was added. When starting material was consumed, the reaction mixture was poured into 1N HCl and extracted with EtOAc (3×), the combined organic layers were dried (MgSO4) and concentrated. Chromatography of the residue (4:1/hexanes:EtOAc) provided the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH2:6][NH:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17].[C:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([N:36]2[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:38][CH2:37]2)[CH:11]=[CH:10][C:9]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(CNc2cc(F)ccc2C(=O)C(F)(F)F)cc(OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)C(F)(F)F)cc(OC)c1
Yield: 135.1 %

Procedure:
A solution of 1-(2-(3,5-dimethoxybenzylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (527 mg, 1.47 mmol), N-Boc-piperazine (296 mg, 1.62 mmol) and N,N-diisopropylethylamine (0.51 mL, 2.94 mmol) in acetonitrile was stirred at reflux for 48 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 1.04 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 230 mg (30%) of tert-butyl 4-(3-(3,5-dimethoxybenzylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate: 1H NMR (400 MHz, CD3OD): δ 9.32 (br t, 1H), 7.63 (dd, 1H), 6.50 (d, 2H), 6.37 (t, 1H), 6.19 (dd, 1H), 5.81 (d, 1H), 4.39 (d, 2H), 3.77 (s, 6H), 3.52-3.49 (m, 4H), 3.35-3.32 (m, 4H), 1.48 (s, 9H). MS (ESI) m/z: Calculated: 523.23; Observed: 546.3 (M++23).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].[OH-].[K+].[CH2:16](Cl)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O.O>[CH2:16]([N:4]1[CH2:3][CH2:2][N:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]1=[O:6])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCC=Cc1ccccc1
Reactant: O=C(NCCCl)Nc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.5 %

Procedure:
To a solution of 20 g of N-(2-chloroethyl)-N'-(3-pyridyl) urea dissolved in 200 ml of dimethyl sulfoxide, 13 g of KOH powder was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Further, 3.4 g of KOH powder was added and then 16.8 g of cinnamyl chloride (trans-form) was added under ice-cooling and the mixture was stirred for 20 minutes, followed by stirring at room temperature for 30 minutes. The mixture was diluted with 300 ml of water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated saline water ad dried, and ethyl acetate was distilled off. To the residue was added 100 ml of 70% acetic acid, and the mixture was heated at 90° C. for 10 minutes and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed twice with saturated saline water and twice with water, and dried. After distilling the ethyl acetate off, the residue was recrystallized from ethanol to give 21.96 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[CH:13]=3)[CH2:9]1)=O)(C)(C)C.C([Li])(C)(C)C.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.CCCCC>[Cl:28][C:15]1[N:16]=[C:17]2[C:12](=[CH:13][C:14]=1[F:22])[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)cnc3N21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: C[C@@H]1CNC[C@H]2Cc3cc(F)c(Cl)nc3N21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
To a solution of 0.23 g (4R,9aR)-7-fluoro-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (intermediate h of examples 54–61) in 5 mL toluene was added dropwise at −78° C. 1.4 mL of a ca 1.3 M solution of t-butyllithium in pentane. The mixture was stirred at −78° C. for 30 min. To the resulting mixture was added 0.3 g hexachloroethane and the mixture was stirred at −78° C. for 30 min and then allowed to thaw to 0° C. over ca 30 min. The reaction was quenched with 10% citric acid and the organic phase was separated and evaporated and the residue purified by chromatography on silica gel with heptane:ethyl acetate (4:1). The product fractions containing the two isomers and some starting material were evaporated and the residue was taken up in 1 mL trifluoroacetic acid and kept at room temperature for 30 min. The solvent was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1). The product fractions containing the more polar isomer were collected evaporated and dried under high vacuum to yield 0.016 g (4R,9aR)-6-chloro-7-fluoro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene as light brown gum.
Reaction SMILES: [OH:1][CH:2]([C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1)[CH:3]([CH3:5])[CH3:4].[NH2:14][C@@H:15]([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1.C(Cl)Cl.CN(C=O)C>O>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:11]([C:8]3[CH:7]=[C:6]([CH:2]([OH:1])[CH:3]([CH3:4])[CH3:5])[O:10][N:9]=3)=[O:13])[CH3:31])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: CC(C)C(O)c1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)C(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Yield: 5.2 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5-(1-hydroxy-2-methyl-propyl)isoxazole-3-carboxylic acid (1.566 mmol, 290 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.044 mmol, 272 mg) using a mixture of DCM (5 ml) and DMF (1 ml) as the solvent. DCM and water were added, the phases were separated and the water phase was extracted with DCM. The combined organics were washed twice with water. The DCM phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 23.4 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 0.94 (d, 3H), 0.98 (d, 3H), 1.23 (d, 3H), 2.06-2.21 (m, 1H), 4.21-4.30 (m, 1H), 4.37-4.46 (m, 1H), 4.51-4.67 (m, 2H), 6.57-6.65 (m, 2H), 7.50 (d, 1H), 7.68 (d, 1H), 7.78-7.86 (m, 1H), 7.97 (d, 1H), 8.04 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]1)=O)(C)(C)C.[CH3:17][Si:18]([CH3:29])([CH3:28])[C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1>>[CH3:28][Si:18]([CH3:17])([CH3:29])[C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24]([O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1cnc(CCCO)c1
Reactant: C[Si](C)(C)C#Cc1ccc(O)cc1
Product: C[Si](C)(C)C#Cc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 4-(3-hydroxypropyl)-1H-imidazole-1-carboxylic acid tert-butyl ester and 5 mmol of 4-(2-(trimethylsilyl)-1-ethynyl)phenol (for the preparation see the literature mentioned in Example 122) are treated as described in Example 122.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Br:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(OC)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(OC)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of compound 53 (22.4 g 123 mmol) in DMF (250 mL) was added N-bromosuccinimide (21.9 g, 123 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 0.5 h. To the mixture was added water and extracted with EtOAc (500 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired compound 54 (27.5 g, 86%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([C:7](=O)[CH:8]([C:14](=O)[C:15]([F:18])([F:17])[F:16])OC2)=[CH:5][CH:4]=1.[CH:21]1[C:26]([NH:27][NH2:28])=[CH:25][CH:24]=[C:23]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:22]=1.Cl.[CH2:34]([OH:36])C>>[F:13][C:12]1[C:11]2[O:36][CH2:34][C:8]3[C:14]([C:15]([F:16])([F:17])[F:18])=[N:28][N:27]([C:26]4[CH:21]=[CH:22][C:23]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:24][CH:25]=4)[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2c(c1F)COC(C(=O)C(F)(F)F)C2=O
Reactant: CCO
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: COc1ccc2c(c1F)OCc1c(C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Yield: 30 %

Procedure:
7-Methoxy-8-fluoro-3-(trifluoroacetyl)isochroman-4-one from Step 3 (450 mg, 1.47 mmol) and 4-sulfonamidophenylhydrazine hydrochloride (430 mg, 1.92 mmol) were dissolved in 5 mL of anhydrous ethanol and heated to reflux for 45 minutes. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 3N hydrochloric acid, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was crystallized from a mixture of isooctane and ethyl acetate to afford 4-[1,4-dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-[1]benzopyrano[4,3-c]pyrazol-1-yl]benzenesulfonamide as a white solid (200 mg, 30%): mp 289.5°-291.0° C.; 1H NMR (acetone d6 /300 MHz) 8.12 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.5 Hz. 2H), 7.07 (dd, J=8.7, 8.5 Hz, 1H), 6.83 (br s, 2H), 6.75 (d, J=8.7 Hz, 1H), 5.45 (s, 2H), 3.90 (s, 3H); 19F NMR (acetone d6 /282 MHz) -62.51 (s) , -140.97 (d). High resolution mass spectrum Calc'd. for C18H13F4N3O4S: 443.0563. Found: 443.0570.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O)=[O:9])=[CH:4][CH:3]=1.[N:23]1([CH2:29][C:30]2[S:34][C:33]([NH2:35])=[N:32][N:31]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:13])[N:35]=[C:33]3[S:34][C:30]([CH2:29][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:31][N:32]3[C:16]=2[OH:18])=[O:9])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C(=O)NCc1ccc(Cl)cc1)C(=O)OCC
Reactant: Nc1nnc(CN2CCOCC2)s1
Solvent: Cc1ccccc1C
Product: O=C(NCc1ccc(Cl)cc1)c1c(O)n2nc(CN3CCOCC3)sc2nc1=O
Yield: 39.1 %

Procedure:
Diethyl 2-(((4-chlorobenzyl)amino)carbonyl)malonate (Preparation 5, 33 mg) and 5-(4-morpholinylmethyl)-1,3,4-thiadiazol-2-ylamine (Preparation 4, 20 mg) are dissolved in xylene and heated to reflux for 5 h. The solvent is evaporated and the residue is triturated with ether. The resulting percipitate is filtered and dried to afford 17 mg of the title compound as a brown solid. Physical characteristics: MS (ESI+) m/z 438 (M+H)+. 1H NMR (DMSO) δ7.42, 7.38, 4.60, 3.92, 3.62, 2.62.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:30]=[O:31])=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:13][CH:12]=1)=[O:10].[CH3:33][Mg]Br>O1CCCC1.C(OCC)C>[Cl:32][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:30]([OH:31])[CH3:33])=[CH:16][N:17]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:13][CH:12]=1)=[O:10]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccc(C(=O)Nc4c(Cl)cncc4Cl)cc32)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C(C)O)c3ccc(C(=O)Nc4c(Cl)cncc4Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1-(toluene-4-sulphonyl)-1H-indole-6-carboxamide (0.1 g, Example 17) in tetrahydofuran (3 ml), at 0° C., was treated with a solution of methylmagnesium bromide in diethyl ether (0.11 ml, 3M). The mixture was allowed to warm to room temperature then stirred for 2 hours. The reaction mixture was quenched with water (15 ml) and then extracted with ethyl acetate (15 ml). The organic extract was dried over sodium sulphate then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (2:1, v/v) to yield the title compound (68 mg) as a white solid, m.p. 206-21 1° C. [Elemental analysis:— C, 55.07; H, 4.00; N, 7.92%. Calculated for C23H19Cl2N3O4S:— C, 54.77; H, 3.80; N, 8.33%].
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:23][CH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[C:27](=[O:43])[N:28]([CH:35]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][C:36]1=[O:42])[C:29]2=[O:34].C(N(CC)CC)C>CN(C=O)C>[O:42]=[C:36]1[CH:35]([N:28]2[C:27](=[O:43])[C:26]3[C:30](=[CH:31][CH:32]=[CH:33][C:25]=3[CH2:24][NH:23][C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[O:9])[C:29]2=[O:34])[CH2:40][CH2:39][C:38](=[O:41])[NH:37]1
Reactant: O=C(O)c1cncnc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cncnc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
A mixture of pyrimidine-5-carboxylic acid (0.25 g, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in DMF (25 mL) was stirred at ambient temperature under nitrogen for 2 hours. 4-Aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were added, and the mixture was allowed to stir for 16 hours. The solvent was evaporated under vacuum, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting with 95:5 methylene chloride-methanol, providing 0.39 g of the product in 50% yield: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.53-2.65 (m, 2H), 2.83-2.91 (m, 1H), 4.98 (d, J=5.7 Hz, 2H), 5.18 (dd, J=12.4 Hz, d=5.4 Hz, 1H), 7.84 (s, 3H), 9.24 (s, 2H), 9.35 (s, 1H), 9.52 (t, J=5.7 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.3, 48.9, 122.1, 127.3, 127.5, 131.6, 133.4, 134.9, 138.4, 156.0, 160.1, 163.5, 167.0, 167.5, 169.8, 172.8; Anal. calcd for C19H15N5O5.0.3H2O: C, 57.23; H, 3.94; N, 17.56. Found: C, 57.27; H, 3.71; N, 17.27.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[C:19](O)=[O:20]>>[O:20]=[C:19]1[C:18]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[N:1][C:2]2[C:7](=[CH:6][CH:5]=[C:4]([S:9]([OH:12])(=[O:10])=[O:11])[CH:3]=2)[NH:8]1
Reactant: Nc1ccc(S(=O)(=O)O)cc1N
Reactant: O=C(O)C(=O)c1cccs1
Product: O=c1[nH]c2ccc(S(=O)(=O)O)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with 3,4-Diamino-benzenesulfonic acid and (thiophen-2-yl)oxo-acetic acid via the method described in Example 12 to afford 2-Oxo-3-thiophen-2-yl-1,2-dihydro-quinoxaline-6-sulfonic acid.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1.[CH3:18][C:19]1[N:23](CCO)[C:22]([N+:27]([O-:29])=[O:28])=[CH:21][N:20]=1.[CH3:30][CH2:31]N=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:18][C:19]1[NH:23][C:22]([N+:27]([O-:29])=[O:28])=[CH:21][N:20]=1.[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([CH3:14])[N:10]=2)[C:6](=[O:7])[C:5]([C:15]([O:17][CH2:30][CH3:31])=[O:16])=[CH:4]1)[CH3:1]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(C)nc21
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CC)c2nc(C)ccc2c1=O
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.5 %

Procedure:
The reaction mixture of nalidixic acid (232 mg, 1.0 mmol), metronidazole (171 mg, 1.0 mmol), EDCI (230 mg, 1.2 mmol), DMAP (20 mg, 0.2 mmol) and THF (5 ml) was stirred at room temperature for 24 h. THF was then removed under reduced pressure. The residue was dissolved in dichloromethane (50 ml). The organic layer was washed with H2O, 5% Na2CO3, H2O, and brine, and then dried over MgSO4. The solvent was removed under vacuum. The resulting solid was recrystallized from C2H5OH and ethyl acetate to give 56 mg 2-methyl-5-nitro-1H-imidazole-1-ethyl 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate. m.p.: 122-124° C.