Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:42][CH3:43]>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([O:33][CH2:42][CH3:43])=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCI
Reactant: CCCCc1nc(C)n(-c2ncc(O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1nc(C)n(-c2ncc(OCC)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Process 1: To the acetonitrile (1 mL) solution of 4′-{[4-butyl-1-(5-hydroxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (68 mg, 0.15 mmol), potassium carbonate (41 mg, 0.30 mmol) and iodoethane (70 mg, 0.448 mmol) were added and stirred at 60° C. for 5 hrs. After that, the reaction mixture was filtered and washed with ethyl acetate. The filtrate was distilled off to obtain 4′-{[4-butyl-1-(5-ethoxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15](=[O:17])[CH3:16])[C@H:10]([CH3:18])[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[C:15]([O:14][C@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:18])(=[O:17])[CH3:16]
Reactant: CC(=O)O[C@H]1CCN(Cc2ccccc2)C[C@H]1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)O[C@H]1CCNC[C@H]1C

Procedure:
A mixture of cis-1-benzyl-4-(RS)-acetoxy-3-(SR)-methylpiperidine [7 g, 28.5 mmole {prepared according to literature procedure described in A. F. Casy and W. K. Jeffery, Can.J.Chem., 50 (1972), 803}] and 20% palladium hydroxide (1.8 g) in methanol (25 ml) was stirred at 50-55° C. under hydrogen (1 atmosphere) for 20 hr. The catalyst was filtered off and washed with methanol. Filtrate was concentrated to give cis-4-(RS)-acetoxy-3-(SR)-methylpiperidine as oil. Yield 4.4 g (99%), C8H15NO2, m/z 158 (M+1), PMR (CDCl3): 0.94 (3H, d, CH3, j=8 Hz), 1.42 (1H, m, H3), 1.67 (1H, m, H5), 1.98 (1H, m, H5), 2.08 (3H, s, COCH3), 2.31 (1H, t, H2, j=12 Hz), 2.68 (1H, dt, H2, j=3 Hz, 12 Hz), 3.04 (2H, m, H6), 4.95 (1H, d, H4, j=6 Hz).
Reaction SMILES: Br[CH2:2][CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([CH:3]2[O:4][CH2:5][CH2:6][N:7]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH2:2]2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C(CBr)OCCNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cccc(C2CN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CCO2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
Dissolve N-[2-[2-bromo-1-(3-methoxyphenyl)ethoxy]ethyl]-4-nitro-benzenesulfonamide (14.22 g, 30.96 moles) in ACN (200 mL); add potassium carbonate (6.42 g, 46.44 mmol); and heat the mixture to reflux. Stir the mixture for 3 h while refluxing. Cool the resulting mixture to ambient temperature and dilute it with EtOAc. Filter through Celite®; concentrate the filtrate under reduced pressure to provide a residue. Purify the residue via flash column chromatography eluting with a 50-80% gradient of EtOAc in hexanes. Combine the product fractions and remove the solvents under reduced pressure to provide the title compound as an orange solid (11.2 g, 95.6%). MS (m/z): 379 (M+1).
Reaction SMILES: CON(C)[C:4](=[O:47])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[C:49]([Mg]Br)([CH3:51])=[CH2:50]>>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=3)(=[O:39])=[O:38])[C@@H:6]([CH2:5][C:4](=[O:47])[C:49]([CH3:51])=[CH2:50])[CH2:11]2)=[CH:17][CH:16]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: C=C(C)[Mg]Br
Product: C=C(C)C(=O)C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
Similar to example 29b, 0.20 g of N-methoxy-2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-N-methyl-acetamide (from example 29c) are reacted with isopropenyl magnesium bromide (0.5M in tetrahydrofuran) to afford the crude title compound as a yellow-brown oil which is used in the next step without any further purification. Rf=0.22 (EtOAc-heptane 1:1); Rt=5.49.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[CH2:20][CH2:19][CH:18]([C:21]([O:23]C)=[O:22])[CH:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+]>CO>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH:17]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)C1CCC(OC(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(OC1CCC(C(=O)O)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 107.5 %

Procedure:
To a solution of 905 mg of methyl 3-(SR)-(1-(RS)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-2-(RS)-phenylcyclopentane-1-(RS)-carboxylate (lower Rf α-methyl isomer) (Racemic 2,3-trans isomer) from Example 8, Step D, Method A in 20 mL of methanol was added 5 mL of 2.0 N sodium hydroxide. After heating at reflux for 2 hours, the methanol was evaporated, and the residual liquid was acidified with 2 N hydrochloric acid. The aqueous phase was washed twice with ethyl acetate. The separate organic layers were washed with brine, combined, dried with sodium sulfate and evaporated to furnish 943 mg of the carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:9][CH:8]2[C:10]([O:12]C(C)(C)C)=[O:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:9][CH:8]2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2CC2C(=O)OC(C)(C)C)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2CC2C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 2-(5-methylthien-2-yl)cyclopropanecarboxylate (100 mg, 0.42 mmol) in CH2Cl2 (3 mL) at RT was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at RT for 10 min and concentrated in vacuo. The crude 2-(5-methylthien-2-yl)cyclopropanecarboxylic acid was used without further purification. M.S.(M+1) 182
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:1]=2)[N:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(=O)CC(=O)CCl
Solvent: CO
Product: COC(=O)Cc1cn2nc(Cl)ccc2n1
Yield: 52 %

Procedure:
10.1 g of 3-amino-6-chloropyridazine was suspended in 120 ml of methanol; 23.5 g of methyl 4-chloroacetoacetate was added, followed by heating and refluxing for 20 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was adjusted to pH 7 by the addition of an aqueous solution of sodium hydrogen carbonate, followed by extraction with ethyl ether; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (1:4). The desired fraction was collected to yield 9.15 g of methyl 6-chloroimidazo[1,2-b]pyridazine-2-acetate was dissolved in 70 ml of N,N-dimethylformamide; while the solution was stirred under ice water cooling conditions, 3.5 g of a 60% sodium hydride dispersion in mineral oil was add little by little, followed by stirring at room temperature for 30 minutes. Under ice water cooling conditions, 6.3 ml of methyl iodide was added, followed by stirring at room temperature for 5 hours. Ice water was poured, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (1:1). The desired fraction was collected and concentrated to yield 14.1 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5]([C:23]#[N:24])=[C:4]([SH:25])[N:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[S:31][CH:32]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[C:5]([C:23]#[N:24])=[C:4]([S:25][CH2:27][C:28]2[N:29]=[C:30]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[S:31][CH:32]=2)[N:3]=1
Reactant: Fc1ccc(Nc2nc(CCl)cs2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2c(C#N)c(N)nc(SCc3csc(Nc4ccc(F)cc4)n3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.20 mmol) of the compound from Example 17A (70% pure) and 130 mg (0.24 mmol) of 4-(chloromethyl)-N-(4-fluorophenyl)-1,3-thiazole-2-amine (from 4-fluorophenylthiourea and 1,3-dichloroacetone) are dissolved in 2.5 ml of dry DMF, and 100 mg (0.98 mmol) of sodium bicarbonate are added. The reaction mixture is stirred at RT for 8 h. After filtration the filtrate is concentrated under reduced pressure and the residue that remains is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:28]1([CH2:34][CH2:35][O:36][C:37]2[CH:38]=[C:39]3[CH:45]=[CH:44][NH:43][C:40]3=[N:41][CH:42]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[OH-].[K+]>CO>[C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:45]2[C:39]3[C:40](=[N:41][CH:42]=[C:37]([O:36][CH2:35][CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:38]=3)[NH:43][CH:44]=2)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C=O)cn1
Reactant: c1cc2cc(OCCN3CCOCC3)cnc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C(O)c2c[nH]c3ncc(OCCN4CCOCC4)cc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A mixture of (5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (19, 315 mg, 0.828 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine (79, 205 mg, 0.829 mmol, prepared as described in Example 29), and potassium hydroxide (70 mg, 1 mmol) in methanol (25 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a yellow solid (80, 0.2 g, 40%). MS (ESI) [M+H+]+=628.42.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2])[CH3:17]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccccc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of acetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic; acid (1.14 mL), ammonium acetate (400 mg), and benzene (50 mL) was heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mL) are added. After an additional 10 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2S04). After filtering, the extract was concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, was isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether, affording an oil that solidified on standing at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:67]([NH:74][CH2:75][CH2:76][CH2:77][NH2:78])([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:78][CH2:77][CH2:76][CH2:75][NH:74][C:67](=[O:68])[O:69][C:70]([CH3:72])([CH3:71])[CH3:73])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous DMF were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-Boc-1,3-propanediamine (57 mg, 0.33 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate as white solid. Yield: 120 mg, 89%.
Reaction SMILES: [NH2:1][C:2](=[O:34])[CH:3]([OH:33])[CH:4]([NH:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CS(C)=O.ClC(Cl)C(O)=O.C([O-])(O)=O.[Na+]>[Cl-].[Na+].O>[NH2:1][C:2](=[O:34])[C:3](=[O:33])[CH:4]([NH:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCOCC2)n1
Agent: O=C(O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.5 %

Procedure:
To a solution of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(3-(morpholinomethyl)-1H-pyrazol-1-yl)nicotinamide (70 mg, 0.151 mmol) in DMSO (3 mL) EDC (240 mg, 1.252 mmol) and—after stirring for 5 min—2,2-dichloroacetic acid (50 μL, 0.609 mmol) were added, and the mixture stirred for 15 min at room temperature. 60 mL of a 1:1 mixture of brine and sat. NaHCO3-solution (60 mL) was added, the stirring continued for 10 min, extracted with ethylacetate (3×50 mL), the combined organic layers dried (MgSO4), filtered off and concentrated in vacuo to give 170 mg of the crude product as yellow oil. Treatment with 15 mL of methyl-tert.butylether (MTB) and further purification of the precipitate formed by chromatography over silica gel (CH2Cl2/methanol) afforded 15 mg of the title compound as amorphous white solid; ESI-MS [M+H]+: 463.2. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.95 (d, 1H), 8.51 (m, 1H), 8.30 (d, 1H), 8.05 (s, 1H), 7.82 (m, 1H), 7.70 (m, 1H), 7.44 (m, 1H), 7.30 (m, 5H), 6.38 (d, 1H), 5.38 (m, 1H), 3.53 (m, 4H), 3.15 and 2.88 (each dd, 1H), 2.29 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Yield: 58.1 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (6.0 g, 20.32 mmol), N-bromosuccinimide (3.80 g, 21.33 mmol) and benzoyl peroxide (246 mg, 1.01 mmol) in CCl4 was refluxed for 1 h. Solid was filtered off through a plug of silica gel. Filtrate was concentrated and purified by silica chromatography, eluting with EtOAc. All fractions contain the desired product was combined and concentrated. Residue was suspended in 150 mL of (3/1) MeOH/EtOAc and was refluxed for 1 h. After cooled, solid was collected, rinsed with MeOH and dried on vacuo to provide the title compound 4.42 g (11.8 mmol) in 58% yield as a white solid. 1H NMR in CDCl3, δ ppm: 11.7 (s, 1H), 8.36 (d, 1H, J=9.2 Hz), 7.63 (d, 1H, J=2.4 Hz), 7.55-7.10 (m, 6H), 4.06 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][N:4]([CH2:8]CC#N)[C:3]1=[O:12].Cl.[C:14]([OH:17])(=[O:16])[CH3:15]>>[CH3:1][N:2]1[C:6](=[O:7])[CH2:5][N:4]([CH2:8][CH2:15][C:14]([OH:17])=[O:16])[C:3]1=[O:12]
Reactant: CN1C(=O)CN(CCC#N)C1=O
Reactant: CC(=O)O
Agent: Cl
Product: CN1C(=O)CN(CCC(=O)O)C1=O
Yield: 49.4 %

Procedure:
334.33 g (2.0 mol) of 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionitrile, prepared as described in Example 5, are hydrolysed for 5 hours and 30 minutes at 96°-107° C. in a mixture of 1482.7 g (13.0 mol) of aqueous 32% hydrochloric acid and 288.3 g (4.8 mol) of acetic acid. The reaction solution is then evaporated at 90° C. under reduced pressure in a rotary evaporator and dried at 120° C./0.1 mbar to constant weight, giving 354.1 g (95.1% of theory) of crude product, which is purified by recrystallization from 1 liter of ethyl acetate, giving 184 g (50.4% of theory) of crystalline 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionic acid having a melting point of 109° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]([C:9]1[NH:25][C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[C:11]=2[CH:10]=1)=O.C([O-])(O)=O.[Na+]>CN(C)C(=O)C>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[NH:17][C:16]1[C:11]2[CH:10]=[C:9]([C:7]#[N:6])[NH:25][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: NC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Product: N#Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
13 ml of phosphorus oxychloride are added to 1.048 g (3.6 mmol) of 6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (see Stage 10.1) and 0.7 ml of N,N-dimethylacetamide. After stirring at RT for 1 h and at 100° C. for 4 h, the reaction mixture is poured into an ice-cooled saturated solution of NaHCO3. Extraction with ethyl acetate (3 times), washing the organic layers with saturated NaHCO3 solution, water and saturated sodium chloride solution, drying (Na2SO4) and concentrating leads to a solid. Column chromatography (SiO2; ethyl acetate), and stirring the crude product in diethyl ether and hexane yields 4-(3-chloroanilino)-6-cyano-7H-pyrrolo[2,3-d]pyrimidine; m.p. 284-287° C.; TLC-Rf=0.71 (CH2Cl2/methanol [10:1]);HPLC: tRet(Grad20)=11.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[CH:25]=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl([O-])=[O:28].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([OH:28])=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(C=O)cc2cc(OCc3ccccc3)cnc21
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCc3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To the solution of 0.41 g (1.2 mmol) 5-benzyloxy-2-formyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester in 10 ml tert-butanol, 7 ml 2-methyl-2-butene and 20 ml acetonitrile, a mixture consistent of 1.2 g (10.6 mmol; 80%) sodium chlorite and 0.97 g (8.1 mmol) sodium dihydrogen phosphate in 10 ml water was added dropwise. The resulting two-phase mixture was stirred 1.5 h at room temperature. Then the organic components were evaporated at a rotary evaporator and the remaining aqueous phase was extracted three times with dichloromethane. The combined organic layers were washed with 10% aqueous sodium thiosulfate solution and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with ethyl acetate: n-heptane (1:1 v/v) as eluant to give 0.35 g (74%) of the compound as a yellow foam.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][Br:13]
Reactant: Cc1ccc2ccccc2c1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccccc2c1Br

Procedure:
A solution of 100 parts of 1-bromo-2-methylnaphthalene, 80.5 parts of N-bromosuccinimide and 0.5 part of benzoyl peroxide in 1500 parts by volume of carbon tetrachloride is heated at reflux temperature for several hours. The solution is then cooled, washed twice with water and the organic layer separated. The organic layer is dried over calcium sulfate, filtered and concentrated to give 1-bromo-2-(bromomethyl)naphthalene, as an oil which solidifies on standing.