Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.Br[CH:17]([CH3:31])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:19]>O1CCOCC1.CN(C=O)C>[N:7]1([CH:17]([CH3:31])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:19])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: CC(Br)C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: c1ccc2[nH]cnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1cccc(C(F)(F)F)c1)n1cnc2ccccc21
Reaction time: 4 h
Yield: 60 %

Procedure:
A solution of potassium tert-butoxide (0.25 mL of 1 M solution in THF, 0.25 mmol) was added to a solution of 1H-benzoimidazole (30 mg, 0.25 mmol) in anhydrous dioxane (10 mL) and anhydrous DMF (1 mL) under argon at ambient temperature. The mixture was stirred for 5 min before a solution of bromo-N-(3-trifluoromethyl-phenyl)-propionamide (59 mg, 0.2 mmol) in anhydrous dioxane (3 mL) was added. The mixture was stirred for 4 h, filtered and concentrated in vacuum. The crude product was purified on a preparative HPLC (XTerra C8 column 19×300 mm, 0.1 M aqueous NH4Ac/CH3CN). Product-containing fractions were pooled and lyophilized to afford 40 mg (60%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.8 (d, J=7.1 Hz, 3H), 5.1 (q, J=7.4 Hz, 1 H), 7.2 (m, 4 H), 7.4 (d, J=7.1 Hz, 1H), 7.5 (m, 2H,) 7.7 (m, 1H), 7.9 (s, 1H), 1/02 (s, 1 H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH:27]=O)[C:26]2[C:20]([CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:19][CH:18]=1.N1CCCC1>C(O)C>[C:17]1(/[CH:27]=[C:10]2\[C:11](=[O:16])[NH:12][C:13]3[C:9]\2=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=3)=[CH:18][CH:19]=[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=[C:26]12
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: O=Cc1ccc2cccccc1-2
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1Nc2ccc(-c3ccccc3)cc2/C1=C/c1ccc2cccccc1-2
Yield: 22.2 %

Procedure:
0.4389 g 5-phenyloxindole (0.0021 mole) and 0.323 g azulene aldehyde (0.0021 mole) were dissolved in 30 mL dried ethanol. 1.5 mL pyrrolidine (1M) was then added and uniformly stirred at reflux temperature for two hours. After removal of dried ethanol, the results were extracted by dichloromethane and citric acid aqueous solution. The organic layer was collected, dried with anhydrous magnesium sulfate, filtered, concentrated under vacuum, and separated by silica gel column chromatography to give Z-form Compound 034 (0.1621 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:18]=[C:17]([F:19])[C:14]([CH:15]=[O:16])=[C:13]([F:20])[CH:12]=3)[C:5]2=[CH:4][N:3]=1.[OH-:22].[Na+].OO.O>>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:20])[C:14]([C:15]([OH:22])=[O:16])=[C:17]([F:19])[CH:18]=3)[C:5]2=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: Cn1nc(-c2cc(F)c(C=O)c(F)c2)c2cnc(N)nc21
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cn1nc(-c2cc(F)c(C(=O)O)c(F)c2)c2cnc(N)nc21
Temperature: 25 °C
Reaction time: 56 h

Procedure:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-benzaldehyde (Example 79) (0.103 g, 0.345 mmol) is suspended in 2M NaOH (0.431 ml, 0.862 mmol), 35% H2O2 in water (17.3 ml, 17.025 mmol) is added and the reaction mixture is stirred at room temperature for 56 hours. The reaction mixture is filtered through filter paper, ice is added to the filtrate and the mixture is quenched with 5M HCl resulting in a white precipitate after 1.5 hours. This solid is collected by filtration, washed with water and dried under vacuum for 24 hours at 45° C. to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH2:9][O:10][C:11]([CH:13]1[C:17](=O)[CH2:16][CH2:15][CH2:14]1)=[O:12].[Cl-].[Ca+2].[Cl-]>C1COCC1>[NH:1]([C:14]1[CH2:15][CH2:16][CH2:17][C:13]=1[C:11]([O:10][CH2:9][CH3:8])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: Nc1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(Nc2ccccc2)CCC1

Procedure:
A mixture of aniline (6.0 g, 64.5 mmol), ethyl cyclopentanone-2-carboxylate (Aldrich Chemicals) (10.0 g, 64.1 mmol) and calcium chloride (7.6 g, 68.5 mmol) in THF (100 ml) was heated under reflux for 24 hours. After being allowed to cool, the suspension was filtered and the solvent was removed from the filtrate under reduced pressure. Kugelrohr distillation of the residue (125° C., 0.02 mmHg) gave the title product as a pale yellow liquid.
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](O)=[O:5].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[F:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[O:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]2[CH:44]=[C:45]([I:47])[S:46][C:39]=12)[NH2:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:29][C:30]1[CH:31]=[C:32]([NH:33][C:4](=[O:5])[CH2:3][C:2]([NH:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:1])[CH:34]=[CH:35][C:36]=1[O:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]2[CH:44]=[C:45]([I:47])[S:46][C:39]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)Nc1ccccc1
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A solution of the acid 1 (465 mg, 2.59 mmol) and BOPCl (666 mg, 2.59 mmol) was mixed in DCM (5 mL) at 0° C. and stirred at the same temperature for 15 min. The reaction mixture was then treated with a solution of 410 (500 mg, 1.29 mmol) and iPr2NEt (1.3 mL, 1 g, 7.79 mmol) in DCM (5 mL) at 0° C. and allowed to stir at room temperature for overnight. The mixture was diluted in DCM (30 mL), washed with saturated NaHCO3 solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using the gradient 75-100% EtOAc in hexanes as an eluent, to provide 411 (382 mg, 54% yield). 1H NMR 6 (400 MHz, CD3OD): 8.33 (d, 5.7 Hz), 7.79 (dd, 1H, J=2.4 Hz, J=12.3 Hz), 7.54 (m, 5H), 7.2-7.4 (m, 4H), 7.09 (t, 1H, J=7.2 Hz), 6.50 (d, 1H, J=5.5 Hz), 3.51 (s, 2H), 7.75 (s, 1H). MS (m/z): (M+1) 547.9 (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13]OC2CCCCO2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.BrCCC[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH2:12][CH2:13][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)CCCOC2CCCCO2)cc1
Reactant: BrCCCCCCCCCCCOC1CCCCO1
Product: Cc1ccc(S(=O)(=O)CCCCCCCCCCCOC2CCCCO2)cc1

Procedure:
As in Example 2a 13.57 g (40.5 mmol) of 1b give, after column chromatography, 13.82 g (83%) of practically colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.Cl.[N:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].Cl.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.O1CCOCC1>[N:20]([C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=3[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)=[CH:25][CH:24]=1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Reactant: CCOc1ccc(I)cc1-c1cc(Cl)nc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: CCOc1ccc(I)cc1-c1cc(Nc2ccc(N=[N+]=[N-])cc2)nc(N)n1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
To a mixture of 4-chloro-6-(5-iodo-2-ethoxy-phenyl)pyrimidin-2-ylamine (7.0 mg, 0.02 mmol) and 4-azidoaniline hydrochloride (5.0 mg, 0.03 mmol) in tert-butanol (1 ml) was added a 1 M hydrogen chloride in dioxane (0.2 ml). The mixture was heated at 90° C. for 2 hours. After cooling to room temperature, the mixture was treated with 1 M aqueous sodium bicarbonate solution (1 ml) and extracted with ethyl acetate (2×1 ml). The combined extracts were concentrated under reduced pressure and the residue was purified by preparative TLC eluting with 35% ethyl acetate-hexane to provide the title compound (6 mg, 68% yield) as a light brown solid. 1H NMR (CDCl3) δ 8.20 (d, J=2.3 Hz, 1H), 7.60 (dd, J=2.3, 8.70 Hz, 1H), 7.38 (d, J=8.70 Hz, 2H), 7.04 (d, J=8.70 Hz, 2H), 6.77 (s, 1H), 6.72 (d, J=5.0 Hz, 1H), 6.63 (br s, 1H), 4.91 (br s, 2H), 4.09 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.CON(C)[C:15]([C:17]1[O:21][CH:20]=[N:19][C:18]=1[CH3:22])=[O:16].[Cl-].[Na+]>C(OCC)C.C(O)C>[CH3:22][C:18]1[N:19]=[CH:20][O:21][C:17]=1[C:15]([C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)=[O:16]
Reactant: Brc1ccoc1
Reactant: CON(C)C(=O)c1ocnc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1ncoc1C(=O)c1ccoc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Bromofuran (2.5 g) in dry diethylether was stirred and cooled to -70° C. under an atmosphere of dry nitrogen and n-butyllithium (2.5M solution in hexane, 6.8 ml) was added dropwise. After 30 minutes, N-methoxy-N-methyl-4-methyl-5-oxazolecarboxamide (2.89 g) in dry diethylether was added dropwise. After a further 30 minutes the mixture was allowed to warm to room temperature. Ethanol (5 ml) was added followed by saturated aqueous sodium chloride. The mixture was extracted with dichloromethane and the material thus obtained was purified by flash chromatography to give the title compound. M.p. 82°-83.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH:11]([S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14])=[CH2:12].C(N(CC)CC)C>CN1C(=O)CCC1>[O:14]=[S:13]1(=[O:15])[CH2:16][CH2:17][N:1]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=2)[CH2:12][CH2:11]1
Reactant: C=CS(=O)(=O)C=C
Reactant: NCCc1ccc(N)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Nc1ccc(CCN2CCS(=O)(=O)CC2)cc1

Procedure:
A mixture of 4-(2-amino-ethyl)-phenylamine (1 g) and ethenesulfonyl-ethene (0.74 ml) in NMP (2.5 ml) containing triethylamine (1.02 ml) was heated to 110 C for 30 mins. The mixture was then allowed to cool and the solid produced was collected by filtration, washed with ether, and dried, giving the title compound as a pale yellow solid (1.59 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:6]3=[N:7][C:2]([C:20]4[S:19][CH:23]=[CH:22][CH:21]=4)=[CH:3][N:4]=[C:5]3[N:10]=[N:9]2)=[CH:13][CH:14]=1
Reactant: OB(O)c1cccs1
Reactant: Fc1ccc(Cn2nnc3ncc(Br)nc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(Cn2nnc3ncc(-c4cccs4)nc32)cc1
Yield: 18.1 %

Procedure:
A mixture of 6-bromo-1-(4-fluoro-benzyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (100 mg, 0.32 mmol), 2-thiopheneboronic acid (44.8 mg, 0.35 mmol), Pd(PPh3)2Cl2 (11.3 mg, 0.016 mmol), and NaHCO3 (80.6 mg, 0.96 mmol) in DME (2 mL) and water (0.4 mL) was put in a microwave reaction tube and reacted in a microwave reactor at 120° C. for 15 minutes. The reaction mixture was partitioned in ethyl acetate and water, and the organic layer was evaporated. The residue was purified on a silica gel column eluting with EtOAc-Hexane to provide 1-(4-fluoro-benzyl)-6-thiophen-2-yl-1H-[1,2,3]triazolo[4,5-b]pyrazine (18 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[N:22]([CH2:23][C:24]([NH:27]C(=O)OC(C)(C)C)([CH3:26])[CH3:25])[C:21]([CH2:35][O:36][CH2:37][CH3:38])=[N:20][C:15]=3[CH:16]=[N:17][C:18]=2[CH:19]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[N:22]([CH2:23][C:24]([NH2:27])([CH3:25])[CH3:26])[C:21]([CH2:35][O:36][CH2:37][CH3:38])=[N:20][C:15]=3[CH:16]=[N:17][C:18]=2[CH:19]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)N
Yield: 92.8 %

Procedure:
HCl in ethanol (3M, 75 mL) was added to tert-butyl [2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate (5.07 g, 10.04 mmol) and the solution was heated at reflux for 15 minutes. The volatiles were removed under reduced pressure and the orange residue was partitioned between dilute aqueous hydrochloric acid and dichloromethane. The aqueous layer was washed with 2 portions of dichloromethane and then made basic with the addition of aqueous ammonium hydroxide. The aqueous fraction was then extracted with three portions of dichloromethane. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to yield 3.77 g of 2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethylamine as a brown oil.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26](=[O:27])[NH:9][CH2:8][C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:10][CH2:11][N:12]([CH:16]([CH3:17])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH3:30]
Reactant: CCOC(N)=O
Reactant: CC(C)N(CCC(CN)(c1ccccc1)c1ccccc1)C(C)C
Product: CCOC(=O)NCC(CCN(C(C)C)C(C)C)(c1ccccc1)c1ccccc1

Procedure:
From 2,2-diphenyl-4-diisopropylamino-butyl-amine in analogy to 3a. The urethane was used in a crude state.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[Cl:12][CH2:13][CH2:14][CH2:15][SH:16].[OH-].[K+]>COCCOC>[Cl:12][CH2:13][CH2:14][CH2:15][S:16][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: SCCCCl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Nc1cc([N+](=O)[O-])ccc1SCCCCl
Yield: 16.5 %

Procedure:
2-amino-4-nitro-fluorbenzene (500 mg, 3.2 mmol), 3-chloro-1 propanethiol (354 mg, 3.2 mmol), and potassium hydroxide (269 mg, 4.8 mmol) were mixed together in ethylene glycol dimethyl ether (6.4 mL) and heated at reflux for 72 hours. The reaction was filtered and the filtercake washed with chloroform. The filtrate was concentrated and purified by flash column chromatography on 10 g if silica gel and eluted with 3% methanol in chloroform to give 2-[(3-chloropropyl)sulfanyl]-5-nitrophenylamine (130 mg, 17%). 1H NMR (CDCl3, 300 MHz): δ7.49-7.48 (m, 2H), 7.38 (dd, 1H, J=7.7 Hz, J=7.7 Hz), 4.55 (s-broad, 2H), 3.64 (t, 2H, J=6.2 Hz), 3.03 (t, 2H, J=7 Hz), 2.00 (q, 2H, J=7 Hz) ppm. Mass Spec (ESI):264 (base M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]1([C:24]([O-])=O)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10]([C:11]3([CH3:24])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)[O-])CC1
Product: CC1(c2nc3cc(F)ccc3o2)CCNCC1

Procedure:
Starting from 2-amino-4-fluorophenol and mono-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (V-9) may be prepared and purified analogously to (V-8) (see 45.1).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:17][C:6]2[C:7]3[NH:8][C:9](=[O:16])[C:10](=[O:15])[NH:11][C:12]=3[CH:13]=[CH:14][C:5]=2[CH2:4]1.[N+:18]([O-])([OH:20])=[O:19]>FC(F)(F)C(O)=O>[ClH:1].[NH2:2][CH:3]1[CH2:17][C:6]2[C:7]3[NH:8][C:9](=[O:16])[C:10](=[O:15])[NH:11][C:12]=3[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:5]=2[CH2:4]1
Reactant: NC1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The parent quinoxalinedione (Example 33) was mixed with 50 mL trifluoroacetic acid and 1 mL fuming nitric acid at 0° C. and stirred for 3 h, then warmed to room temperature for 2 h. The solvent was evaporated, the residue taken up in acetone, and the solid collected by filtration. After washing with water and then tetrahydrofuran, the material was dried to give 1.3 g of the compound as the hydrochloride salt. CHN calc'd for C11H10N4O4.HCl.0.5H2O; C, 38.39; H, 3.52; N, 16.28; found-C, 38.54; H, 3.57; N, 17.39. CI MS m/e (M+1) 263. H-NMR (400 MHz, dmso) 1H, s, 12.2; 1H, s, 12.12; 2H, br s, 8.1; 1H, s, 7.9; 1H, br s, 4.2: 1H, dd, 3.7; 2H, m, 3.4; 1H dd, 3.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)=[C:9]([Cl:28])[CH:8]=1>N1C=CC=CC=1>[Cl:28][C:9]1[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][C:10]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1
Reactant: Nc1ccc(CCN2CCN(c3ccc(N)cc3Cl)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(c3ccc(NS(C)(=O)=O)cc3Cl)CC2)cc1
Yield: 64.2 %

Procedure:
The title compound (0.52 g), was prepared similarly to the procedure of Example 1(C) from methanesulphonyl chloride (0.44 g), 1-(4-amino-2-chlorophenyl)-4-(4-aminophenethyl)piperazine (0.55 g), and pyridine (10 ml).
Reaction SMILES: [C:1]([CH:6]=[C:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=2[F:30])[CH2:9][CH2:8]1)([O:3][CH2:4][CH3:5])=[O:2].[I-].[CH3:32][S+](C)(C)=O.CC(C)([O-])C.[K+]>CS(C)=O>[C:1]([CH:6]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]4=[O:29])=[CH:15][C:14]=3[F:30])[CH2:11][CH2:12]2)[CH2:32]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=C1CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC12CCN(c1ccc(N3C[C@H](CNC(C)=O)OC3=O)cc1F)CC2
Yield: 61 %

Procedure:
The title compound was prepared by reacting (S)—N-[3-{4-[4-carboethoxymethylidene piperidin-1-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-ylmethyl]acetamide (1.0 mmol, Example E), trimethyloxosulphonium iodide (1.3 mmol), potassium tert-butoxide (1.3 mmol) in dimethylsulfoxide (10 ml) at a temperature 25° C. for 14 hours in 61% yield.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[N:10]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:9]=2)[C:5]([C:31]#[N:32])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[N:10]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:9]=2)[C:5]([C:31]#[N:32])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Cl)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
2-hydroxy-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (880.2 mg, 1.916 mmol) was cooled down with an ice bath. Phosphorus oxychloride (2.938 g, 1.786 mL, 19.16 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes at 0° C. and then allowed to warm up to rt and stirred at room temperature for 18 hours. The reaction mixture was quenched by slow addition onto ice. After 1 hour of stirring, the mixture was extracted into ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a pale orange solid. The solid was triturated further in EtOAc and filtered off (715.4 mg, 78% yield)
Reaction SMILES: B.C1COCC1.[CH2:7]([N:14]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[C:22]#[N:23])[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:29]>C1COCC1.CCOCC>[ClH:28].[ClH:29].[CH2:7]([N:14]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22][NH2:23])[CH3:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCCOc1cccc(Cl)c1C#N)Cc1ccccc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(CCCOc1cccc(Cl)c1CN)Cc1ccccc1
Temperature: 25 °C

Procedure:
Borane/THF (165 ml of a 1M solution) was added with stirring to a solution of 2-[3-(N-benzyl-N-methylamino)propoxy]-6-chlorobenzonitrile (13.01 g) in dry THF (100 ml) under nitrogen at ambient temperature. The mixture was boiled under reflux for 5 hours and then evaporated to dryness. The residue was heated on a steam bath under nitrogen for 2 hours, then cooled to ambient temperature. 1M Hydrochloric acid (100 ml) was added and the mixture was heated on a steam bath for 2 hours. The mixture was cooled in ice and basified with concentrated sodium hydroxide solution and then extracted with dichloromethane to give an oil. The oil was dissolved in ether and treated with ethereal hydrogen chloride to give a solid which was collected by filtration and recrystallised from propan-2-ol/IMS (2:1) to give 2-[3-(N-benzyl-N-methylamino)propoxy]-6-chlorobenzylamine dihydrochloride, m.p. 226°-228° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][C:12]=2[CH3:22])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:30]1([CH2:33][NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:32][CH2:31]1>C(O)C>[CH:35]1([N:34]([CH2:33][CH:30]2[CH2:31][CH2:32]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH3:19])(=[O:21])=[O:20])=[CH:13][C:12]=3[CH3:22])=[O:9])[CH:3]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: C1CCC(NCC2CC2)CC1
Reactant: CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Temperature: 160 °C
Yield: 69.7 %

Procedure:
A solution of 6-chloro-N-(2-methyl-4-(N-methylsulfamoyl)phenyl)pyrimidine-4-carboxamide (Intermediate 37, 80 mg; 0.235 mmol) and diisopropylamine (82 mL; 0.47 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (49.1 mg; 0.29 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and then filtered. The solid was washed with a 1:1 mixture of water:ethanol and allowed to dry to give the title compound as a white solid (75 mg, 70%).