Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]([CH3:8])([CH3:7])[CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[O:15]=[C:16]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH:17]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.[I-].[K+]>[C:5]([C:3]([CH2:2][N:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:18][CH:17]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C:16]1=[O:15])=[O:4])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)NC1CN(C2CCCC2)c2ccccc2NC1=O
Reactant: CC(C)(C)C(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C2CCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
Bromomethyl tert-butylketone (684 mg), potassium iodide (26.4 mg), tetra n-butylammonium bromide (30.8 mg) and potassium carbonate (528 mg) were added successively to a solution of 2-oxo-3-tert-butoxycarbonylamino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.1 g) in N,N-dimethylformamide (30 ml), the mixture was stirred at room temperature for 2 hours. Ice-water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with saturated brine. The resultant mixture was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and n-hexane was added to the residue for crystallization, collected by filtration, to thereby obtain 1.07 g of the title compound.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH2:9]([O:11][C:12](=[O:20])[C:13]#[C:14][C:15](OCC)=[O:16])[CH3:10]>CO>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([OH:16])[C:4]2[C:3](=[CH:2][C:1]([CH3:8])=[CH:6][CH:5]=2)[N:7]=1)=[O:20])[CH3:10]
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CO
Product: CCOC(=O)c1cc(O)c2ccc(C)cc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 15.5 g of m-Tolylamine in 130 ml of methanol, 24.6 g of but-2-ynedioic acid diethyl ester was added drop-wise over 30 min at 0° C. and stirred for 3 h at RT. Then, the solvents were removed under reduced pressure and the residue was dissolved in 70 ml of Dowtherm® and heated to 250° C. for 2 h. Then, the reaction mixture was allowed to cool to RT and 300 ml of n-heptane was added to precipitate the crude product, which was collected by filtration. The title compound was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 9.7 g.
Reaction SMILES: CC(C)(O[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=O)C.F[C:40](F)(F)C(O)=O>ClCCl>[CH3:40][N:7]([CH3:5])[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:24]([N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Yield: 97 %

Procedure:
9.6 g (18.3 mmol) of 1-[N6-[(1,1-dimethylethoxy)carbonyl]-N2-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine were stirred overnight in 200 ml of a 5% solution of trifluoroacetic acid in dichloromethane. The reaction mixture was then evaporated down in vacuo. 13.47 g (97% of theory) of the desired 1-[N2-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine were obtained as the trifluoroacetate salt. Then 7.0 g (9.1 mmol) of the crude product were dissolved in 200 ml of water and 4.1 ml of a 40% formaldehyde solution (45.6 mmol) were added whilst cooling with an ice bath. The reaction mixture was stirred for 10 minutes at room temperature, carefully mixed with 1.5 g (40 mmol) of sodium borohydride whilst cooling with an ice bath, then mixed with 4.1 ml of a 40% formaldehyde solution (45.6 mmol) whilst cooling externally with ice, after which the reaction mixture was stirred for a further 10 minutes at room temperature and again mixed with 1.5 g (40 mmol) of sodium borohydride whilst cooling with an ice bath. The pH of the reaction mixture was monitored continuously during the reaction and kept between pH 3 and pH 6 by dropwise addition of trifluoroacetic acid. The mixture was then stirred for 30 minutes at 5° C., adjusted to pH 10 by the addition of potassium carbonate and extracted four times with 50 ml of ethyl acetate. The combined organic phases were dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc. aqueous ammonia=6.5/3/0.3 (v/v/v)). 2.3 g (56% of theory) of a colourless oil were obtained.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:37]C(=O)OC(C)(C)C)([CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]([F:36])([F:35])[F:34])=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10]2)[CH2:4][O:3]1.CC1(C)OCC(NC(=O)OC(C)(C)C)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:37][C:5]([CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:34])[F:35])=[CH:23][CH:22]=3)[CH:15]=2)[CH2:10]1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(OCc4ccc(-c5ccccc5C(F)(F)F)cc4)ccc3C2)COC(C)(C)OC1
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Product: NC(CO)(CO)CN1CCc2cc(OCc3ccc(-c4ccccc4C(F)(F)F)cc3)ccc2C1
Yield: 75 %

Procedure:
When the product of Step C was substituted for tert-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate in Example 1, Step B, the identical process afforded the title compound in 75% yield, as an off white solid. 1H-NMR (CDCl3+CD3OD) 2.5-3.9 (m, 16H+H2O); 5.02 (s, 2H); 6.69-6.91 (m, 3H); 7.25-7.53 (m, 7H); 7.68 (d, 1H, J=7.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[I:8].[Br-].[CH2:17]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:18][CH3:19].CC(C)([O-])C.[K+].O>C1COCC1>[CH:17](=[C:12]1[CH2:13][CH2:14][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:10][CH2:11]1)[CH2:18][CH3:19]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2ccc(I)c(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC=C1CCC(c2ccc(I)c(F)c2)CC1
Temperature: -10 °C

Procedure:
44.95 g of 4-(3-fluoro-4-iodophenyl)cyclohexanone and 55.4 g of propyltriphenylphosphonium bromide were introduced into 250 ml of THF, and the mixture was cooled to -10° C. with stirring and under nitrogen. A solution of 15.8 g of potassium tert-butoxide in 150 ml of THF was then added dropwise at -10° C. with stirring, and the mixture was then stirred at room temperature for a further 2 hours. The yellow suspension was then cooled to 10° C., and 500 ml of water were added. The organic phase was separated off, and the aqueous phase was extracted once with 100 ml of methyl tert-butyl ether. The combined organic extracts were washed once with 100 ml of water, dried using sodium sulfate, filtered and evaporated to a residue. The residue was then purified by means of a silica-gel frit, and the eluate was evaporated to a residue, giving 4-(4-propylidenecyclohexyl)-2-fluoro-1-iodobenzene.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[CH2:27]([O:31][C:32]([NH:34][C@H:35]([CH2:40]O)[C:36]([F:39])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:29][CH3:30]>ClCCl>[CH2:27]([O:31][C:32]([NH:34][CH:35]([C:36]([F:39])([CH3:38])[CH3:37])[CH2:40][I:20])=[O:33])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCOC(=O)N[C@H](CO)C(C)(C)F
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCOC(=O)NC(CI)C(C)(C)F
Yield: 78.6 %

Procedure:
To a well-stirred mixture of polystyryl supported triphenylphosphine (29.3 mmol) in dry dichloromethane (40 mL) under a nitrogen atmosphere was added iodine (7.44 g, 29.3 mmol). After ten minutes, imidazole (2.0 g, 29.3 mmol) was added, followed in ten minutes by a solution of N-butoxycarbonyl-3-fluorovalinol (13.3 mmol) in dichloromethane (200 mL). The mixture was heated to reflux for two hours. The cooled mixture was filtered through celite and the filtrate was evaporated. The residue was dissolved in diethyl ether (150 mL), and this solution was washed with dilute aqueous sodium thiosulfate (1×75 mL) and water (2×75 mL). The organic layer was dried (Na2SO4), filtered through a pad of silica gel and evaporated to afford 3.46 g of N-butoxycarbonyl-1-iodo-2-amino-3-fluoro-3-methyl-n-butane: 1H NMR (CDCl3) δ4.72 (br d, 1H), 3.86 (br m, 1H), 3.56 (dd, 1H), 1.47 (s, 9H), 1.43 (m, 6H) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=[O:4].[OH-].[Na+]>CO>[CH:10]1([C:9]2[N:8]([C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[N:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:11][CH2:12]1
Reactant: COC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
hydrolyzing the 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester with methanol in the presence of sodium hydroxide at reflux to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid;
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.2 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(1-pyrrolidinylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 12) (356 mg, 0.85 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (288 mg).
Reaction SMILES: [CH2:1]([N:8]=[C:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][Mg]Cl.CCOCC.O>C1COCC1>[CH2:1]([NH:8][C:9]1([CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[F:23])[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccccc1C[Mg]Cl
Reactant: CC(C)(C)OC(=O)NC1CCCC(=NCc2ccccc2)C1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCC(Cc2ccccc2F)(NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of tert-butyl 3-(benzylimino)cyclohexylcarbamate (4 mmol) in THF (10 mL) was added a solution of (2-fluorobenzyl)magnesium chloride in ether (9 mmol, 0.25 M, 36 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for overnight. The reaction mixture was added to the iced water. The organics were extracted using EtOAc from the aqueous mixture. The EtOAc solution was concentrated. The product, tert-butyl 3-(benzylamino)-3-(2-fluorobenzyl)cyclohexylcarbamate, was purified by column chromatography on silica gel.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:36][CH2:35][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[S:27][C:26]5[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C:21]=5[CH:20]=4)=[O:18])[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO>[ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:36][CH2:35][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[S:27][C:26]5[CH2:25][CH2:24][NH:23][CH2:22][C:21]=5[CH:20]=4)=[O:18])[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)cc2C1
Agent: Cl
Solvent: CO
Product: O=C(c1cc2c(s1)CCNC2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Reaction time: 0.5 h

Procedure:
Hydrogen chloride in methanol (2.3 ml, 2.82 mmol, 1.25 mol/l) was added at room temperature to a solution of tert-butyl 2-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (280 mg, 0.564 mmol) in methanol (2 ml), and the reaction mixture was refluxed for 2 h. The solvent was removed in vacuo, the residue was taken up in a small amount of ethanol (3 ml), and diethyl ether (50 ml) was added thereto. Cooling was then carried out for 30 min. in an ice bath, and the resulting solid was filtered out, washed with diethyl ether and dried in vacuo. Yield: 180 mg (73%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH3:16]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:14][C:21]([NH:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])=[S:22])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ncccc1-c1ccc(F)cc1
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ncccc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(4-fluoro-phenyl)-pyridin-2-ylamine (200 mg, 1.06 mmol) in dioxane (10 mL) was added ethoxycarbonyl isothiocyanate (141 μL, 1.17 mmol) and stirred at room temperature for 12 hours. The solvent was evaporated and the residue was used for the next step without purification. The title compound was obtained as a light yellow solid (340 mg, 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17]>[OH-].[Na+]>[CH3:19][O:18][C:16]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)NC(C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of L-valine, d8 (Cambridge Isotope Laboratories, 0.4949 g) in 1N sodium hydroxide (3.95 mL) was added sodium carbonate (0.419 g). The solution was cooled to 0° C. and methyl chloroformate (0.289 mL) was added dropwise over 30 minutes and reaction mixture was stirred for 3 h at 0° C. Reaction mixture was washed with ethyl ether (3×15 mL) and aqueous layer was acidified to pH=1 with concentrated HCl. Aqueous layer was extracted dichloromethane (3×15 mL) and organic layers were dried (MgSO4) and concentrated to give 2-Methoxycarbonylamino-3-methyl-butyric acid, d8 as a white solid (0.5681 g).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:31]=1[Cl:38]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[C:31]([Cl:38])=[CH:32][CH:33]=[C:34]([F:37])[C:35]=3[F:36])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Reactant: Fc1ccc(Cl)c(CBr)c1F
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2c(Cl)ccc(F)c2F)cc1

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(bromomethyl)-1-chloro-3,4-difluorobenzene in a manner similar to that described in Example 25 as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.68-7.62 (m, 1 H), 7.44-7.39 (m, 1 H), 7.35 (d, J=7.8 Hz, 2 H), 7.31-7.25 (m, 1 H), 7.12 (d, J=3.5 Hz, 1 H), 6.96 (dd, J=8.4, 10.5 Hz, 1 H), 6.29 (d, J=3.5 Hz, 1 H), 5.64-5.52 (m, 3 H), 2.75 (s, 3 H), 2.48 (s, 3 H), 0.96 (s, 9 H); LCMS (m/z) ES+=513 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([N:11]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[S:37][CH:38]=[CH:39][N:40]=4)=[C:30]([Cl:41])[CH:29]=3)[O:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:41][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:12]4[O:13][CH:14]5[CH2:15][NH:8][CH2:9][CH:10]5[N:11]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1
Reactant: CC(C)(C)OC(=O)N1CC2N=C(Nc3ccc4ncnc(Nc5ccc(OCc6nccs6)c(Cl)c5)c4c3)OC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Nc2ncnc3ccc(NC4=NC5CNCC5O4)cc23)ccc1OCc1nccs1

Procedure:
N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3 aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine is prepared from 2-{4-[3-chloro-4-(thiazol-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydro-pyrrolo[3,4-d]oxazole-5-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride. MS APCI (+) m/z 494, 496 (M+1, Cl pattern) detected; 1H NMR (400 mHz, CD3OD) δ 8.44 (s, 1H), 8.19 (br. s, 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.67 (m, 3H), 7.58 (dd, 1H), 7.22 (d, 1H), 5.50 (s, 2H), 5.17 (m, 1H), 4.76 (m, 1H), 3.32 (d, 1H), 3.16 (d, 1H), 2.85 (m, 2H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([OH:17])[C@@H:12]1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC=C)(=[O:21])[CH3:20]>>[C:19]([O:17][C@H:13]1[C@H:12]([OH:18])[C@@H:11]([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:16][CH:15]=[CH:14]1)(=[O:21])[CH3:20]
Reactant: C=COC(C)=O
Reactant: O=C(OC[C@H]1OC=C[C@@H](O)[C@@H]1O)c1ccccc1
Product: CC(=O)O[C@@H]1C=CO[C@H](COC(=O)c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
1.0 g (4 mmol) of 6-O-benzoylglucal is taken up in 10-20 ml of vinyl acetate and stirred with 1 g of lipase (Pseudomonas spec.) at room temperature for 5 h. Filtering off the enzyme and crystallization or chromatography on silica gel (ethyl acetate/hexane 1:1) yields 3-O-acetyl-6-O-benzoylglucal in 88-94% yield (1.03-1.10 g).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[C:44]3[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=3)[CH2:38][N:37]([CH3:47])[CH2:36]2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[Cl:45][C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([Cl:46])[CH:41]=1)[CH2:38][N:37]([CH3:47])[CH2:36][CH:35]2[C:32]1[CH:31]=[CH:30][C:29]([S:26]([NH:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH:35]4[C:44]5[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=5)[CH2:38][N:37]([CH3:47])[CH2:36]4)=[CH:33][CH:34]=3)(=[O:28])=[O:27])=[O:12])=[CH:10][CH:9]=2)(=[O:28])=[O:27])=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)c3ccc(C(=O)NCCOCCOCCOCCNS(=O)(=O)c4ccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)cc4)cc3)cc2)C1
Yield: 50.7 %

Procedure:
Compound 233 was prepared following the procedures outlined in Example 215 using terephthalic acid (10.4 mg, 0.0628 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 82, 97.2 mg, 0.1255 mmol). Purification by preparative HPLC gave the title compound (38.9 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.83 (m, 10H), 7.85 (s, 2H), 7.42 (d, 4H), 6.83 (s, 1H), 3.66-3.55 (m, 28H), 3.46-3.39 (m, 11H), 3.12 (s, 7H), 3.04 (t, 4H). MS (m/z): 1223.14 [M+H]+.
Reaction SMILES: C(NC1C=C([C:11]2[C:16]([C:17]([C:19]3[C:20]([C:25]4C=CC=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=4)=NC=C[CH:24]=3)=O)=[CH:15][CH:14]=[CH:13][N:12]=2)C=CC=1)(=O)C.[Br-].[C:36]([CH2:39][CH2:40][CH2:41][CH2:42][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:38])=[O:37].CC(C)([O-])C.[K+].O>O1CCCC1>[C:32]([NH:31][C:27]1[CH:24]=[C:19]([C:17]([C:16]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:42][CH2:41][CH2:40][CH2:39][C:36]([OH:38])=[O:37])[CH:20]=[CH:25][CH:26]=1)(=[O:34])[CH3:33]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1cccc(-c2ncccc2C(=O)c2cccnc2-c2cccc(NC(C)=O)c2)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=CCCCC(=O)O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At -25° C., 94 g of 3-acetylaminophenyl-3-pyridylketone are added to a mixture of 217 g of 4-carboxybutyl-triphenylphosphonium bromide and 154 g of potassium tert.butoxide in 1.8 litres of tetrahydrofuran. After 2 hours stirring at ambient temperature, 200 ml of water are added to the reaction mixture and then it is evaporated down. The residue is taken up in 500 ml of water and washed with ethyl acetate. The agueous phase is then neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is evaporated down and the residue is recrystallised from ethyl acetate/acetone.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH:3]=1
Reactant: O=c1[nH]cc(Cl)c2ccccc12
Reactant: O=S(=O)(O)Cl
Product: O=c1[nH]cc(Cl)c2ccc(S(=O)(=O)Cl)cc12
Temperature: 100 °C
Yield: 58.6 %

Procedure:
4-Chloro-1-(2H)-isoquinolone (20.62 g, 115 mmol) was added portionwise to stirred chlorosulphonic acid (61 mL, 918 mmol) at 0° C. The mixture was heated at 100° C. for 3.5 d and then cooled to room temperature. The reaction mixture was added in small portions onto ice-water [CAUTION] and the resulting precipitate was collected by filtration. The solid was washed with water, triturated with MeCN and then dried in vacuo to give 4-chloro-7-chlorosulphonyl-1-(2H)-isoquinolone (18.75 g, 67.4 mmol) as a cream solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1.Cl>O1CCOCC1>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cnc(OCC(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of methyl 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate (200 mg, 0.847 mmol) in Dioxane (1.2 mL) was added aqueous 2N HCl (1.0 mL). The reaction was stirred at 80° C. for 16 hrs. The reaction was concentrated in vacuo to afford the title compound quantitatively (188 mg, 0.847 mmol). MS m/z=223.1 (M+H).