Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH2:10][CH2:11][CH2:12][CH2:13][B:14]1[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH2:1]([C:4]([N:23]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH3:31])([CH2:10][CH2:11][CH2:12][CH2:13][B:14]1[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:21])([CH3:22])[O:15]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C=CCC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)OCC)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Ethyl 2-allyl-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.64 g, 1.50 mmol) was dissolved in THF (5 mL) and cooled to 0° C. NaHMDS (1 M solution in THF, 2.5 mL, 2.5 mmol) was added dropwise and the reaction was stirred for 20 min. Methyl iodide (0.47 mL, 7.5 mmol) was added and the reaction was warmed to room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl solution (5 mL), diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 2-25% ethyl acetate in heptane to afford the desired product (0.518 g, 79%). Rf 0.53 (30% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 5.78-5.62 (m, 1H), 5.15-5.03 (m, 2H), 4.12 (q, J=9.0 Hz, 2H), 2.90 (s, 3H), 2.89-2.81 (m, 1H), 2.58-2.51 (m, 1H), 1.94-1.83 (m, 1H), 1.76-1.66 (m, 1H), 1.54-1.08 (m, 29H), 0.77 (t, J=8.0 Hz, 2H). ESI MS found for C23H42B1N1O6 m/z [440.2 (M+1)].
Reaction SMILES: N1CCC[CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9](=[O:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)C>>[Cl:7][CH2:8][C:9](=[O:18])[C:10](=[CH:2][CH3:3])[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)CC(=O)CCl
Agent: CC=O
Product: CC=C(C(=O)CCl)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 6 h

Procedure:
1.5 ml of piperidine are added dropwise to a stirred mixture of 212 g (1.1 mol) of tert.-butyl 4-chloro-3-oxobutyrate and 97 g (2.2 mol) of acetaldehyde at -20° C. under nitrogen. The mixture is subsequently stirred at -20° C. for six hours and is then worked up analogously to Example 2. Crude yield: 210 g, content according to gas chromatography: 6% of starting material, 52+37% of an isomer mixture of the product. The product is further processed in the crude form.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:18]=[CH:17]2>ClCCCl.C(O)(C)(C)C>[C:26]1([S:23]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([NH:13][C:5]4[C:4]5[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=5)[N:8]=[CH:7][N:6]=4)=[CH:22][CH:21]=3)[CH:17]=[CH:18]2)(=[O:24])=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(I)cc34)ccc21
Yield: 74.8 %

Procedure:
6-iodo-4-chloroquinazoline (2.38 g, 8.20 mmol) and 5-amino-1-benzenesulfonylindole (2.46 g, 9.00 mmol) were combined in DCE (20 mL) and t-butanol (20 mL). The resulting mixture was heated at reflux under nitrogen for 18 hours to form a bright yellow suspension. Upon cooling the solids were filtered and rinsed with CH2Cl2 and placed under high vacuum to remove any excess solvent. Quinazoline 14 (3.23g, 75%) was obtained as a yellow solid. 1H NMR (DMSO d6; 400 MHz): δ: 9.24 (s, 1H, NH), 8.84 (s, 1H), 8.33 (dd, 1H, 8.9 Hz, 1.7 Hz), 8.01 (m, 4H), 7.90 (m, 2H), 7.70 (m, 2H), 7.60 (m, 3H), 6.92 (dd, 1 H, J=3.7 Hz, 0.6 Hz).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([N:35]1[C:39](=[O:40])[CH:38]=[CH:37][C:36]1=[O:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:17]([N:35]1[C:36](=[O:41])[CH2:37][CH:38]([O:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:39]1=[O:40])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCCCCN1C(=O)C=CC1=O
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN1C(=O)CC(ON(Cc2ccccc2)Cc2ccccc2)C1=O

Procedure:
The procedure of Example 1 is repeated using 6.10 g (29 mmole) of N,N-dibenzylhydroxylamine and 10.0 g (29 mmole) of N-n-octadecylmaleimide. The residue is purified by preparative HPLC (Silica gel: 9:1 heptane:ethyl acetate eluent) to give 8.0 g (49%) of a waxy solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11]Br.[C-:13]#[N:14].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:13]#[N:14]
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1ccc(Br)c(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCc1cc([N+](=O)[O-])ccc1Br
Yield: 34 %

Procedure:
A solution of 1-bromo-2-(bromomethyl)-4-nitrobenzene (54 g, 183 mmol) in toluene (200 mL) and water (100 mL) was heated to 60° C., then NaCN (27.2 g, 555 mmol) was added, followed by stirring at reflux overnight. Water was added to the mixture, the aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1 to 5:1) to give 2-(2-bromo-5-nitrophenyl)acetonitrile (15 g, yield 34%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=C(C#N)[C:5]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[OH-:15].[Na+].[CH3:17][CH2:18][OH:19]>>[CH3:1][C:2]1[N:7]=[C:17]([C:18]([OH:15])=[O:19])[C:5]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1ccc(-n2nccn2)c(C#N)n1
Agent: [Na+]
Product: Cc1ccc(-n2nccn2)c(C(=O)O)n1
Temperature: 100 °C

Procedure:
To a solution of the title compound of Step A (730 mg, 4 mmol) in EtOH (10 mL) was added 4 N NaOH (1 mL, 4 mmol). The mixture was heated at 100° C. for 24 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:17]1([C:22](=O)[CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(OCC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]1([C:22](=[N:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(=O)C1CCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=N[C@H](C)c1ccccc1)C1CCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(R)-1-Phenylethanamine (1.36 ml, 1.2 mmol) and triethylamine (7.46 ml, 53.5 mmol) were dissolved in DCM (30 ml) and cooled to 0° C. Titanium tetrachloride (0.49 ml, 4.46 mmol) was added, followed by the solution of 1-cyclopentyl-ethanone (1 g, 8.92 mmol) in DCM (5 ml). The reaction mixture was stirred 3 h at reflux temperature. After cooling to rt diethylether was added (130 ml) and the reaction mixture was filtered. The filtrate was collected and the solvents were evaporated at reduced pressure to give the product as yellow, viscous oil (2.04 g, crude quantitative). [1H-NMR (DMSO-d6, 600 MHz) δ 7.35 (d, 2H), 7.28 (t, 2H), 7.17 (t, 1H), 4.61 (q, 1H), 2.67-2.62 (m, 1H), 1.81 (s, 3H), 1.71-1.50 (m, 8H), 1.27 (d, 3H); LCMS RtL=2.706 min; [M+H]+=216.2]
Reaction SMILES: C([C:3](=[C:9]([O:15][CH2:16][CH3:17])[CH:10]=[CH:11][N:12](C)[CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#N.CC(O)=[O:20]>>[CH2:16]([O:15][C:9]1[CH:10]=[CH:11][NH:12][C:13](=[O:20])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:17]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C#N)=C(C=CN(C)C)OCC
Product: CCOC(=O)c1c(OCC)cc[nH]c1=O
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of ethyl 2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (150 g, 0.63 mol) and HOAc (600 mL) was refluxed overnight. The mixture was cooled to RT, concentrated to dryness, treated with water and washed with EtOAc (2×). The aqueous layer was made basic (pH=9-10) with NaHCO3, extracted with DCM (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography to afford ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (90 g, 67% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1OS(C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccccc2)nc1N1CCCCC1
Temperature: 80 °C
Yield: 96 %

Procedure:
To a solution of the above-prepared 2-phenyl-4-trifluoromethanesulfonyloxy-thiazole-5-carboxylic acid ethyl ester (0.75 mmol) in toluene (5 mL) was added piperidine (4.5 mmol). The reaction mixture was heated to 80° C. for 2 hours. The mixture was then diluted in ethyl acetate, washed successively with water and brine, and dried over MgSO4. Silica gel chromatography of the crude mixture provided title compound (96%) as a yellowish oil.
Reaction SMILES: [C:1]([C:4]1[C:14]([OH:15])=[CH:13][C:12]2[CH:11]3[CH2:16][CH:7]([CH2:8][N:9]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:10]3)[C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>CO.O>[F:20][C:18]([F:21])([F:19])[C:17]([N:9]1[CH2:10][CH:11]2[CH2:16][CH:7]([C:6]3[CH:5]=[C:4]([C:1](=[N:24][OH:25])[CH3:2])[C:14]([OH:15])=[CH:13][C:12]=32)[CH2:8]1)=[O:22]
Reactant: NO
Reactant: CC(=O)c1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1
Yield: 89.1 %

Procedure:
1-(4-Acetyl-5-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (190 mg, 0.605 mmol), hydroxylamine HCl (99 mg, 1.21 mmol) and sodium acetate (118 mg, 1.21 mmol) were combined in methanol (4 mL) and H2O (1 mL) and warmed to 65° C. for 18 hours. The mixture was cooled, diluted with H2O and extracted with ethyl acetate which was dried (Na2SO4), filtered and concentrated to provide a yellow oil (177 mg, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[CH:7][C:6]=1F)[CH3:2].[CH:27]([NH2:30])([CH3:29])[CH3:28]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[CH:7][C:6]=1[NH:30][CH:27]([CH3:29])[CH3:28])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(N2CCC(NC(=O)OC(C)(C)C)C2)cc1F
Reactant: CC(C)N
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(N2CCC(NC(=O)OC(C)(C)C)C2)cc1NC(C)C
Yield: 28.1 %

Procedure:
4-[3-(tert-Butoxycarbonylamino)-pyrrolidin-1-yl]-2,5-difluorobenzoic acid ethyl ester (Example 2j, 5.4 g, 13.9 mmol), isopropylamine (40 mL, 469 mmol), and dimethyl sulfoxide (25 mL) are heated at 100° C. for 4 days in a sealed glass tube. The excess amine is removed by blowing in compressed air. The residue is filtered and concentrated under vacuum to a thick oil. Purification by column chromatography (1:1:7 ethyl acetate/chloroform/hexanes) to provide the title compound as a solid (1.6 g). MS: m/z 410 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([N:9]1[C:10]2[C:6](=[C:5]3[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]3=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2Cl)c2c1OCCN(C(=O)OC(C)(C)C)C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-chlorobenzenesulfonyl chloride (24 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2-chlorophenyl)sulfonyl]-6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (6 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (5.8 mg). MS m/z 407 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[OH:13][CH:14]1[CH:18]([OH:19])[CH:17]([CH2:20][OH:21])N[C:15]1=[O:22].C(=O)(O)[O-].[Na+]>CO.O.C(O)(=O)C>[CH2:1]([N:8]1[C@H:17]([CH2:20][OH:21])[C@@H:18]([OH:19])[C@@H:14]([OH:13])[C:15]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(CO)C(O)C1O
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C1[C@H](O)[C@H](O)[C@@H](CO)N1Cc1ccccc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6 (15.2 g) was dissolved in methanol (85 ml) and acetic acid (3.1 g) and benzylamine (5.4 g) added. Sodium cyanoborohydride (3.1 g) was then added and the mixture kept at room temperature for 24 hours to reduce the imine to an amine 3. Sodium bicarbonate (6 g) and water 20 ml was added and the mixture heated for 4 hours at 70° C. to effect cyclization to the lactam 7. The mixture was concentrated to a syrup and partitioned between ethyl acetate (300 ml) and cold saturated sodium chloride (100 ml). The ethyl acetate layer was recovered, dried (sodium sulfate) and concentrated to a syrup. The syrup was dissolved in methanol (200 ml) to which was added potassium carbonate 20 g and water 2 ml. The resulting mixture was stirred at room temperature for 14 hours, filtered, the filtrate concentrated and the resulting syrup dissolved in methanol (400 ml). Concentrated HCl (4.1 ml) was added. A white solid was formed. This was removed by filtration and the filtrate concentrated to dryness. Methanol was added again and the solution again concentrated. This was repeated one more time to give the crude N-benzyl pyrrolidone which can be converted to the pyrrolidine to reduction.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)CN(c1ncccn1)Cc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.1 %

Procedure:
A mixture of the amine from example 4 (200 mg, 0.53 mmol), 2-chloropyrimidine (66 mg, 0.58 mmol) and potassium carbonate (72 mg, 0.53 mmol) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 18 hours. TLC analysis showed starting materials remained, so additional 2-chloropyrimidine (66 mg, 0.58 mmol) was added, and the reaction was stirred at 80° C. for a further 72 hours. The cooled mixture was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and brine, and the layers were separated. The organic layer was washed with water, wash with ammonium chloride solution, dried over magnesium sulphate and then evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluant, to afford the title compound as a yellow oil (117 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([N+]([O-])=O)=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccccc3F)nc3ncccc23)c2ccncc12
Reactant: OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Fc1ccccc1-c1cc(-c2ccc(OCCN3CCOCC3)c3cnccc23)c2cccnc2n1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A solution of 198 mg (0.50 mmol) 2-(2-fluoro-phenyl)-4-(8-nitro-isoquinolin-5-yl)-[1,8]naphthyridine (synthesis see example 6) and 131 mg (1.00 mmol) 4-(2-hydroxyethyl)morpholine in 1 ml dioxane was treated with 326 mg (1.00 mmol) cesium carbonate (3.0 mmol). The resulting slurry was stirred at 80° C. for three days. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-(2-fluoro-phenyl)-4-[8-(2-morpholin-4-yl-ethoxy)-isoquinolin-5-yl]-[1,8]naphthyridine as colourless solid; HPLC/MS: 1.37 min, [M+H] 481.
Reaction SMILES: O=[C:2]1[C:7](=O)[NH:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[NH:3]1.S(Cl)([Cl:15])=O.[ClH:17]>CN(C)C=O>[Cl:17][C:2]1[C:7]([Cl:15])=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cl
Reactant: N#Cc1[nH]c(=O)c(=O)[nH]c1C#N
Solvent: CN(C)C=O
Product: N#Cc1nc(Cl)c(Cl)nc1C#N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
FIG. 13 shows the reaction pathway. This reaction should be carried out in a fume hood. In a 500 mL round-bottomed flask with a 24/40 ground-glass joint attached to an efficient reflux condenser and under a nitrogen atmosphere, a magnetically stirred slurry consisting of 8.10 g (0.050 mol) of 1,4,5,6-tetrahydro-5,6-dioxo-2,3-pyrazinedicarbonitrile, 4.0 mL of dimethylformamide 306 and 160 mL of thionyl chloride 1301 was heated. Gas evolution began at ca. 62° [SO2 & HCl gasses evolved]. After about 3.5 hours, the solid had dissolved and the temperature had risen to 70°. After cooling to room temperature, a Dry Ice/acetone bath was applied until the temperature of the reaction medium was −65°. The crystals which formed were collected by rapid filtration of the cold slurry through a sintered-glass filter under a nitrogen blanket. The solid was washed twice with 150-ml portions of cold diethyl ether and air-dried to give 7 g (70%) of 2,3-dichloro-5,6-dicyanopyrazine 301, mp 180-182°. Crystallization of the product may be accomplished if dark, from ˜50 mL of chloroform with carbon treatment to give 5.5 g of purified product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH3:25].[Cl-].[Al+3].[Cl-].[Cl-].C(O)(C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([CH3:15])[C:17]=2[CH3:25])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: Cc1cc2ccccc2n1C
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CC(C)O
Product: Cc1c(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)c2ccccc2n1C

Procedure:
is obtained as described in Example 10 (a) from 10 g 4-chloro-3-sulfamoylbenzoyl chloride and 6.53 g 1,2-dimethylindole in dichloro-ethane in the presence of 12 g aluminum chloride. After treatment with isopropanol, crystals having a melting point of 247°-249° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].N1C=CC=CC=1.O1CCCC1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)=[O:8])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1)c1ccccc1
Reaction time: 1 h
Yield: 25.8 %

Procedure:
Under argon atmosphere, a mixture of 5-amino-N-[3,5-bis(trifluoromethyl)-phenyl]-2-hydroxybenzamide (364 mg, 1 mmol), pyridine (95 mg, 1.2 mmol) and tetrahydrofuran (10 mL) was cooled on ice. Benzoyl chloride (155 mg, 1.1 mmol) was added, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (121 mg, 25.7%) as a white solid.
Reaction SMILES: [C:1](N)(C)(C)C.[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][C@H:14]([O:18][CH:19]([CH3:21])[CH3:20])[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=1.S(=O)(=O)(O)O.C(OC)(C)(C)C>CO>[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][C@H:14]([O:18][CH:19]([CH3:21])[CH3:20])[C:15]([O:17][CH3:1])=[O:16])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)N
Reactant: CC(C)O[C@@H](Cc1cccc(O)c1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H](Cc1cccc(O)c1)OC(C)C
Temperature: 10 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
(2S)-3-(3-Hydroxyphenyl)-2-isopropoxypropionic acid tert-butylamine salt (8.2 kg, 28 mol) was dissolved in methanol (41 L), and then the reaction mixture was cooled to 10° C. Concentrated sulfuric acid (1.9 L, 36 mol) was added to the reaction mixture at 10 to 20° C. over a period of 5 minutes. The reaction mixture was stirred at 60° C. for 3 hours, followed by adding tert-butylmethyl ether (164 L) and a 10% sodium chloride solution (41 L) to separate an organic layer. Then, the organic layer was washed sequentially with the 10% sodium chloride solution (41 L), a 7% sodium bicarbonate aqueous solution (16 L), and water (41 L), followed by vacuum concentration to obtain 6.62 kg of the title compound (yield: 100%). The 1H-NMR data thereof coincided with that of the compound of Example 1-(5).