Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][CH2:4][C@H:3]1[NH:6][C:7]1[C:8]([CH3:27])=[N:9][C:10]2[C:15]([N:16]=1)=[C:14]([C:17]1[NH:25][C:24]3[CH2:23][CH2:22][NH:21][C:20](=[O:26])[C:19]=3[CH:18]=1)[CH:13]=[CH:12][CH:11]=2.CCN(C(C)C)C(C)C.[CH3:37][C:38](OC(C)=O)=[O:39]>C(Cl)Cl>[CH3:27][C:8]1[C:7]([NH:6][C@H:3]2[CH2:4][CH2:5][C@H:2]2[NH:1][C:38](=[O:39])[CH3:37])=[N:16][C:15]2[C:10]([N:9]=1)=[CH:11][CH:12]=[CH:13][C:14]=2[C:17]1[NH:25][C:24]2[CH2:23][CH2:22][NH:21][C:20](=[O:26])[C:19]=2[CH:18]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CC[C@@H]1N
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CC[C@@H]1Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
Prepared according to Example 50, using rac-2-(3-((cis-2-aminocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Ex. 54, 120 mg, 0.331 mmol) and DIPEA (0.173 ml, 0.993 mmol, and Ac2O (0.034 ml, 0.364 mmol) in DCM (13.2 mL, and stirring at 25° C. for 2.5 h. Purification by column chromatography (silica gel) provided rac-N-(cis-2-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)cyclobutyl)acetamide (68.3 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91-11.99 (1H, m) 8.20-8.24 (1H, m) 7.88 (1H, d, J=1.00 Hz) 7.55-7.60 (1H, m) 7.49-7.53 (1H, m) 7.34 (1H, t, J=1.00 Hz) 7.30 (1H, s) 7.03 (1H, s) 4.48-4.59 (2H, m) 3.44-3.51 (2H, m) 2.84-3.02 (3H, m) 2.54 (3H, s) 2.25-2.35 (1H, m) 2.09-2.19 (1H, m) 1.91 (1H, s) 1.70 (1H, s) 1.58-1.67 (1H, m). m/z (ESI, +ve) 405.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:38])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][C:33]3[NH:34][CH:35]=[CH:36][N:37]=3)[CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>N1C=CC=CC=1>[CH3:39][N:40]([CH3:44])[C:41]([N:37]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:32][N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:16](=[O:38])[NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=2)=[CH:22][CH:21]=1)[CH2:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1)=[O:42]
Reactant: CN(C)C(=O)Cl
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2)cc1
Solvent: c1ccncc1
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nccn3C)Cc3nccn3C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42 %

Procedure:
The compound (95.0 mg) obtained in Example 49-1, was dissolved in pyridine (5.0 ml) and added with N,N-dimethylcarbamoyl chloride (20.0 mg). After the solution had been stirred at room temperature for 15 hours, pyridine was distilled off and the residue was then added with a saturated aqueous sodium bicarbonate solution and extracted with chloroform. The extract was concentrated and purified through column chromatography (chloroform/methanol), thereby obtaining the subject compound (45.4 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)=[O:5].O.O.Cl[Sn]Cl.Cl>C(O)C>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH2:14])[CH:8]=1)=[O:5]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)cc1F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(NC(=O)c2ccc(F)cc2F)ccc1F
Yield: 89.2 %

Procedure:
Using a method similar to Preparation 14 using 2,4-Difluoro-N-(4-fluoro-3-nitrophenyl)benzamide (Preparation 13) (1.0 g, 3.38 mmol), SnCl2.2H2O (3.8 g, 16.9 mmol), ethanol (25 mL), and concentrated HCl (25 mL), gives the title intermediate (803 mg, 89% yield): mass spectrum (ion spray): m/z=267.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:18][C:19]([OH:21])=[O:20].[O:22]1[C:26](B(O)O)=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2>>[O:22]1[C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[CH:25]=[C:26]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:18][C:19]([OH:21])=[O:20]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: O=C(O)Cc1cn(Cc2ccccc2)c2ccc(Br)cc12
Product: O=C(O)Cc1cn(Cc2ccccc2)c2ccc(-c3cc4ccccc4o3)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 78 except that 2-[5-bromo-1-benzyl-1H-indol-3-yl]acetic acid and benzo[b]furan-2-boronic acid were used.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](O)[CH:9](O)[CH3:10]>>[CH3:10][C:9]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:1][CH:8]=1
Reactant: Nc1ccccc1
Reactant: CC(O)CO
Product: Cc1c[nH]c2ccccc12

Procedure:
Aniline and propylene glycol were reacted at a molar ratio shown in Table 17 in the same manner as described in Example 1, whereby 3-methylindole was obtained as a main product. The results are shown in the following Table 17.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([CH3:14])[CH3:13].C(O)C.[H][H]>[Pd].O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)=C1C(=O)Nc2ccc(O)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C1C(=O)Nc2ccc(O)cc21
Yield: 81 %

Procedure:
23 g. 5-Hydroxy-3-isopropylideneindolinone are dissolved in 100 ml. ethanol and 150 ml. tetrahydrofuran and hydrogenated in the presence of 1 g. 10% palladium-charcoal at ambient temperature and 1 bar hydrogen pressure. After filtering off the catalyst with suction, the filtrate is distilled off in a vacuum and the residue is triturated with diethyl ether and filtered off with suction. There are obtained 19 g. of the title compound; yield 81% of theory; m.p. 175° C.
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:45](O)[CH2:46][OH:47]>O>[CH2:45]1[CH2:46][O:47][CH:7]2[CH:8]([C@@H:9]([C@@H:5]([CH2:4][CH2:3][CH:2]([OH:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:21]1
Reactant: OCCO
Reactant: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC

Procedure:
A solution of 3.4 g. of ethyl 15-hydroxy-9-oxo-prostanoate (Example 50) in 85 ml. of benzene containing 30 mg. of p-toluenesulfonic acid monohydrate and 2 ml. of ethylene glycol is stirred at the reflux temperature for 18 hours. The water formed is removed by means of a Dean-Stark distilling receiver. The cooled solution is washed with 5% aqueous sodium carbonate solution, saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 3.78 g. (99%) of oil; λ max. 2.93 (hydroxy group) and 5.77 μ (ester carbonyl group).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:40][CH:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)=[O:28])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a mixture of 0.11 g (0.27 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-20), 0.19 mL (1.1 mmole) of ethyldiisopropyl amine and 0.034 g (0.30 mmole) of 4-amino-1-methyl-piperidine in 3.0 mL of dimethylformamide was added 0.13 g (0.30 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-75:25) gave 0.10 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-21) as a white solid.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:34])[NH:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)[N:13]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].I[CH3:49].O>O1CCCC1>[Si:3]([O:10][C@H:11]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:34])[N:25]([CH3:49])[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)[N:13]1[C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)NCCc3ccccn3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCc1ccccn1)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
NaH (8.38 mg of a 60 wt % dispersion in mineral oil, 0.210 mmol) was added to a stirred, room temperature mixture of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-{[2-(pyridine-2-yl)ethyl]carbamoyl}benzyl)pyrrolidine-1-carboxylate (120 mg, 0.191 mmol) in tetrahydrofuran (1.9 mL), and the mixture was stirred for 30 minutes. After 30 minutes, iodomethane (0.014 mL, 0.23 mmol) was added and the mixture was stirred for 12 hours. Water was then added and the mixture was partitioned with EtOAc. The aqueous extracts were extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give the product as an orange oil that was used directly in the next step. LC-MS=644.3 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:10]2[CH:6]([CH2:7][NH:8][CH2:9]2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([OH:11])[CH:4]([OH:20])[CH2:3]1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32](O)=[O:33])=[CH:23]1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl.ON1C2C=CC=CC=2N=N1>[CH3:1][C:2]1([CH3:21])[CH:10]2[CH:6]([CH2:7][N:8]([C:32](=[O:33])[CH2:31][C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][CH:23]=3)[CH2:9]2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([OH:11])[CH:4]([OH:20])[CH2:3]1
Reactant: COc1ccccc1C1(O)C(O)CC(C)(C)C2CNCC21
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C1(O)C(O)CC(C)(C)C2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.9 %

Procedure:
To a solution of 0.44 g of (3aRS,4RS,5RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol and 0.29 g of 3-indoleacetic acid in 40 cm3 of dichloromethane, cooled to 0° C., are added 5 mg of 1-hydroxybenzotriazole, 0.35 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.42 cm3 of diisopropylethylamine. The mixture is stirred for 15 hours at room temperature, 100 cm3 of dichloromethane are added and the organic phase is washed with 50 cm3 of aqueous sodium bicarbonate solution and with 60 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The cream-coloured foam obtained is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 1 cm, height 30 cm), eluting under a pressure of 0.5 bar nitrogen with a mixture of dichloromethane and methanol (97/3 by volume) and collecting 30 cm3 fractions. Fractions 5 to 7 are combined and then concentrated to dryness under reduced pressure (2.7 kPa); the solid obtained is recrystallized in 5 cm3 of isopropyl ether. 0.48 g of (3aRS,4RS,5RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[(3-indolyl)acetyl]-4,5-perhydroisoindolediol is obtained, melting at 160-165° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8](Cl)[N:7]=1)=[O:5])[CH3:2].ClC(Cl)C(O)=[O:17].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[O:17])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Cl)ccc1C
Reactant: O=C(O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1[nH]c(=O)ccc1C
Temperature: 25 °C

Procedure:
A mixture of 6-chloro-3-methyl-pyridine-2-carboxylic acid ethyl ester (650 mg, 3.26 mmol), dichloroacetic acid (5 mL) and water (0.5 mL) was refluxed for 1 h. After cooling to r.t., the mixture was neutralized with saturated NaHCO3 and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 230 mg of the title compound as a white solid. MS: (+) m/z 182.25 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].O1CCCC1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=1[CH3:19]>O>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:2]([O:4][CH3:5])=[O:3])[C:13]=1[CH3:19]
Reactant: COC(=O)Cl
Reactant: Cc1c(N)cccc1Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Nc1cccc(Cl)c1C
Temperature: 25 °C

Procedure:
Under cooling, to a mixture of methyl chloroformate 30 mL and tetrahydrofuran 50 mL was added dropwise 1-chloro-2-methyl-3-aminobenzene 5.00 g and the mixtures were stirred at 25° C. for a half hour. To the reaction mixtures was added water and the resulting mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The mixtures were concentrated under reduced pressure to give 1-chloro-2-methyl-3-methoxycarbonylaminobenzene 5.80 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:21]([OH:23])=O)[N:15]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:16]=2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:56]1([CH2:62][CH2:63][CH2:64][NH2:65])[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:21]([NH:65][CH2:64][CH2:63][CH2:62][N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:23])[N:15]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:16]=2)=[O:10])=[C:4]([CH3:24])[CH:3]=1
Reactant: NCCCN1CCOCC1
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(CC2CC2)c(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(CC2CC2)c(C(=O)NCCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
34.8 mg (0.1 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-(cyclopropylmethyl)-1H-imidazole-2-carboxylic acid (Example 4A) are dissolved in 0.3 ml of DMF and, after addition of 39.7 mg (0.1 mmol) of HBTU and 10.12 mg (14 μl; 0.1 mmol) of triethylamine, stirred at room temperature for 30 minutes. This solution is added to a solution of 28.8 mg (0.2 mmol) of (3-morpholin-4-ylpropyl)amine in 0.1 ml of DMF and shaken overnight. After filtration, the reaction mixture is purified by preparative HPLC (column: Macherey-Nagel VP 50/21 Nucleodur C18 gravity, 5 μm; flow rate: 25 ml/min; eluent A: acetonitrile, eluent B: water+0.1% conc. aqueous ammonia solution, gradient: 0 min 10% A, 2.00 min 10% A, 6.00 min 90% A, 7.00 min 90% A, 7.10 min 10% A, 8 min 10% A; running time: ca. 10 min per separation; wave length: 220 nm). The correct fractions are evaporated in vacuo.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:39])[C@H:19]([C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3C(OC(C)(C)C)=O)[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:5]2[CH:11]=[N:10][NH:9][C:6]2=[N:7][CH:8]=1>O1CCOCC1.C(Cl)Cl>[ClH:2].[ClH:1].[Cl:2][C:3]1[C:4]([N:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:39])[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[CH2:16][CH2:17]2)=[C:5]2[CH:11]=[N:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(Cl)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C([C@@H](c1ccc(Cl)cc1)[C@@H]1CCCN1)N1CCN(c2c(Cl)cnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
4N HCl in dioxane (2 mL) was added to a solution of (S)-tert-butyl 2-((S)-2-(4-(5-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-(4-chlorophenyl)-2-oxoethyl)pyrrolidine-1-carboxylate (90 mg, 0.16 mmol) in CH2Cl2 (1 ml). The mixture was stirred at room temperature for 30 minutes. After 30 minutes, the solvent was removed in vacuo, and the resulting residue was triturated with ether. The solid material was filtered, washed with additional ether (2×2 mL) and dried to provide (S)-1-(4-(5-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (71 mg, 0.13 mmol, 83% yield) as a cream solid. LCMS (APCI+) m/z 459.1, 461.1 [(M+H]+. NMR (400 Hz, DMSO-d6) δ 9.61 (br s, 1H), 9.08 (br s, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 7.49 (d, 2H), 7.44 (d, 2H), 4.53 (d, 1H), 4.03-3.96 (m, 1H), 3.79-3.70 (m, 3H), 3.69-3.57 (m, 3H), 3.51-3.45 (m, 1H), 3.21-3.14 (m, 2H), 3.09-3.00 (m, 1H), 1.97-1.89 (m, 1H), 1.78-1.71 (m, 1H), 1.63-1.52 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=O)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[S:37])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCOc1cccc(C(CNCC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CCCCOc1cccc(C(CNCC(=S)N(C)C)C(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a solution of 2-[2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamino]-N,N-dimethylacetamide (0.38 g, 1.0 mmol) in dry toluene (20 ml), Lawesson's reagent (0.58 g, 1.2 mmol) was added one-pot and the mixture was heated to reflux and stirred for 2 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (petroleum ether:AcOEt from 9:1 to 8:2) to give pure title compound as a colourless oil (0.11 g, 28% yield).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.N1C=CC=CC=1>C(OCC)(=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: Nc1nccs1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 4-nitrophenyl chloroformate, 5.04 g (25 mMole), in 25 ml of dry ethyl acetate was added dropwise to an ice cooled, stirred solution of 2-aminothiazole, 5.01 g (50 mMole) in dry ethyl acetate, 25 ml, and dry pyridine, 50 ml. The ice bath was removed as the reaction mixture became viscous. Stirring was continued at 22° C. for three hours. Ethyl acetate was added. The insolubles were filtered, rinsed with ethyl acetate, with water, with acetone, dried and recrystallized from acetone furnishing 3.55 g of 2-(4-nitrophenoxycarbonyl)aminothiazole, m.p 211°-212° C. dec, which was characterized by nuclear magnetic resonance, mass spectra, infrared spectra and elemental analyses.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: C=CC(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)CCNc1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
Under nitrogen, 4-benzyloxyaniline (13.0 g, 65 mmol) was dissolved by heating at 70° C., and a boron trifluoride-diethyl ether complex (0.82 mL, 6.5 mmol) was added dropwise at the same temperature to the dissolved solution. Methyl acrylate (5.85 mL, 65 mmol) was then slowly added dropwise to the resulting solution. This solution was stirred for 10 hours at 70° C. After cooling with ice, ethyl acetate was added to the reaction mixture and washed with aqueous 1 N sodium hydroxide and brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 17.5 g of the title compound.
Reaction SMILES: CON(C)[C:4](=[O:17])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][CH2:7][CH3:8].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[O:17]=[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:6][CH2:7][CH3:8]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 50 mL round-bottomed flask was (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopentan-2-ylcarbamate (91d, 250 mg, 0.96 mmol) dissolved in THF (9.6 ml). Phenylmagnesium bromide (2.88 ml, 2.88 mmol) 1.0 M in THF was added. The reaction was stirred at r.t. for 5 h. The reaction was poured into a mixture of saturated ammonium chloride and ethyl acetate. The mixture was shaken and the layers separated. The water layer was washed twice with ethyl acetate. The combined organic layers were washed once with a small portion of water and dried over sodium sulphate. The solvent was evaporated and the crude product was purified by flash chromatography.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([OH:17])([C:13]([O:15][CH3:16])=[O:14])[CH2:6][C:7]=1[C:8](=[O:12])[CH2:9][CH2:10][CH3:11].O.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1>O.O1CCCC1>[C:8]([CH:7]1[CH2:6][C:5]([OH:17])([C:13]([O:15][CH3:16])=[O:14])[CH:4]=[CH:3][C:2]1=[O:26])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)C1=C(N)C=CC(O)(C(=O)OC)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)C1CC(O)(C(=O)OC)C=CC1=O
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 4-amino-5-butyryl-1-hydroxycyclohexa-2,4-diene-1-carboxylate (1.25 g, 5.2 mmol) in a 1:1 mixture of water/tetrahydrofuran (10 mL) was added p-toluenesulfonic acid monohydrate (1.1 g, 5.8 mmol). The reaction mixture was stirred for 18 h and then partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford methyl 5-butyryl-1-hydroxy-4-oxocyclohex-2-ene-1-carboxylate which was used without further purification or characterization.