Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:41]5[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][OH:46])[CH2:39][CH2:40]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: OCCN1CCNCC1
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(CCO)CC1
Yield: 32.1 %

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) and 2-piperazin-1-yl-ethanol (135 mL, 1.104 mmol) were reacted as described in Example 73. Isolated yield of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea (75 mg, 32%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.55 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.25 (m, 5H), 6.50 (s, 1H), 4.40 (s, 1H), 4.25 (m, 2H), 4.00 (s, 3H), 3.45 (m, 2H), 2.50-2.25 (m, 12H), 1.95 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 636 (M+H)+.
Reaction SMILES: [C:1]1([CH2:11][C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[C:1]1([CH2:11][C:12]([NH:14][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Cc1cccc2ccccc12
Reactant: Ic1ccsc1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Cc1cccc2ccccc12)Nc1ccsc1
Reaction time: 18 h
Yield: 94.9 %

Procedure:
2-(naphthalen-1-yl)acetamide (14.00 g, 75.6 mmol), 3-iodothiophene (10.15 g, 48.3 mmol), trans-1,2diaminocyclohexane (3.0 ml, 25.0 mmol), cuprous iodide (1.97 g, 10.3 mmol), and potassium carbonate (13.66 g, 98.8 mmol) in dioxane (50 ml) was placed into a preheated oil bath at 95° C. After stirring for 18 h, the heterogenous mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was flash chromatographed with 19:1, 9:1, 17:3, and 4:1 methylene chloride:ethyl acetate as the eluant to yield 12.26 g (95% yield) of 2-(naphthalen-1-yl)-N-(thiophen-3-yl)acetamide as a brown solid. Method [7] Retention time 2.07 min by HPLC (MH+ 268).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=C)=[CH:19][CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.C[N+]1([O-])CC[O:30]CC1>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:11]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:25])=[CH:18][CH:19]=1)=[O:30]
Reactant: C=Cc1ccc(CN(CCCCCCC(=O)OCC)S(C)(=O)=O)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N(CCCCCCC(=O)O)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of ethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate (2.2 g, 6.0 mmol) in dioxane (45 mL) was added to a solution of N-methylmorpholine N-oxide (1.47 g, 12.5 mmol) in water (45 mL). Osmium tetroxide (4.6 mL, 2.5 wt % in 2-methyl-2-propanol) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched with 1N HCl (50 mL) and the aqueous solution was extracted with CH2Cl2. The organic layer was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 35% aqueous THF (100 mL) and NalO4 (1.41 g, 6.59 mmol) was added. The mixture was stirred at room temperature for 2 h and was diluted with EtOAc and water. The organic solution was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (1.9 g) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 7.82-7.90 (d, 1H), 7.50-7.59 (d, 2H), 5.30 (s, 2H), 4.45 (s, 2H), 4.05-4.18 (m, 2H), 3.12-3.22 (m, 2H), 2.86 (s, 3H), 2.19-2.30 (m, 2H), 1.42-1.62 (m, 6H), 1.18-1.30 (m, 3H); MS 387 (M+18).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:34](=[O:37])[CH2:35][CH3:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O:38]=[C:39]1[CH2:42][N:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:40]1>C1COCC1>[OH:38][C:39]1([C@@H:35]([CH3:36])[C:34](=[O:37])[N:29]2[C@@H:28]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:32][O:31][C:30]2=[O:33])[CH2:42][N:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:40]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To a solution of diisopropylamine (6.5 mL, 46.3 mmol) in THF (200 mL) at −78° C. was added butyllithium (17 mL of a 2.5 M solution in hexanes, 42.5 mmol) over 5 min. The solution of lithium diisopropylamide was stirred for 15 min at −78° C. A solution of (S)-4-benzyl-3-propionyl-2-oxazolidinone (9.0 g, 38.6 mmol) in THF (100 mL) was added to the lithium diisopropylamide by addition funnel over 26 min. The reaction temperature was kept below −70° C. during the course of the addition. After the addition, the mixture was stirred for a further 30 min at −78° C. Then phenylmethyl 3-oxoazetidine-1-carboxylate (9.5 g, 46.3 mmol) was added by addition funnel over 25 minutes as a solution in THF (100 mL). Again, the reaction mixture was kept below −70° C. during the reagent addition. After stirring for an additional 1 hour at −78° C., the reaction mixture was quenched with saturated ammonium chloride solution and was then allowed to warm to rt. Water was added to dissolve any precipitated ammonium chloride, and ethyl acetate was added. The layers were partitioned, and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (50% ethyl acetate: 50% hexanes) to provide phenylmethyl 3-hydroxy-3-{(1R)-1-methyl-2-oxo-2-[(4S)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]ethyl}azetidine-1-carboxylate as a white crystalline solid (6.03 g, 13.8 mmol, 36% yield). 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 8H), 7.20 (d, 2H), 5.12 (s, 2H), 4.66 (m, 1H), 4.27-4.20 (m, 2H), 4.10 (q, 1H), 4.03-3.93 (m, 3H), 3.28 (dd, 1H), 2.77 (dd, 1H), 1.29 (d, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc2occc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1cc2cc(CN3CCCCC3)ccc2o1

Procedure:
1-Benzofuran-5-carbaldehyde was treated with piperidine and sodium triacetoxyborohydride under the standard reductive amination protocol to provide 1-(5-benzofuranylmethyl)piperidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18](=[O:19])[CH:17]3[CH:20]([C:25]([OH:27])=[O:26])[CH:21]4O[C:16]3([CH:23]=[CH:22]4)[CH:15]2[CH3:28])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl>[CH3:28][CH:15]1[C:16]2[CH:23]=[CH:22][CH:21]=[C:20]([C:25]([OH:27])=[O:26])[C:17]=2[C:18](=[O:19])[N:14]1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC1N(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C2C(C(=O)O)C3C=CC21O3
Agent: Cl
Product: CC1c2cccc(C(=O)O)c2C(=O)N1C1CCNCC1
Yield: 82.5 %

Procedure:
3-(1-Tert-butoxycarbonyl-piperidin-4-yl)-2-methyl-4-oxo-10-oxa-3-aza-tricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid (6.6 g, 16.8 mmol) was dissolved in aqueous 37% hydrochloric acid (80 mL) and the resulted solution was refluxed for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with methanol and decanted in order to obtained the desired product as white solid (3.8 g, 82%).
Reaction SMILES: [N:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:21])[CH2:19][CH3:20]>ClCCl>[N:10]1[CH:11]=[CH:12][C:7]([N:6]([N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[C:18](=[O:21])[CH2:19][CH3:20])=[CH:8][CH:9]=1
Reactant: c1ccn(Nc2ccncc2)c1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)N(c1ccncc1)n1cccc1

Procedure:
To a solution containing 2.9 g of N-(1H-pyrrol-1-yl)-4-pyridinamine and 5 g of sodium bicarbonate in 100 ml of dichloromethane was added a solution containing 1.9 g of propionyl chloride in 20 ml of dichloromethane.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]2[C:20]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:19][CH:18]=[CH:17][N:16]2[CH:27]=1.[Br:28]NC(=O)CCC(N)=O>C(Cl)Cl>[Br:28][C:17]1[N:16]2[CH:27]=[C:13]([CH2:12][O:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[N:14]=[C:15]2[C:20]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:19][CH:18]=1
Reactant: c1ccc2nc(OCc3cn4ccnc(N5CCOCC5)c4n3)ccc2c1
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClCCl
Product: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of compound 31a (5.0 g, 14 mmol) and N-bromosuccinamide (2.5 g, 14 mmol) in DCM (300 mL) at 0° C. was allowed to stir at rt for 10 min. The reaction mixture was diluted with DCM (600 mL) and washed with saturated NaHCO3 (500 mL) and brine (500 mL). The DCM layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was triturated with EtOAc to give compound 31b as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H18BrN5O2: 440.1 (M+H). found: 440.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8].[N+:16]([O-])([OH:18])=[O:17]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[C:10]([N+:16]([O-:18])=[O:17])[C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1sc2cc(O)c(O)cc2c1Cl
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Chloro-5,6-dihydroxy-benzo[b]thiophene-2-carboxylic acid was dissolved in ethyl acetate and a solution of nitric acid in dichloromethane (2M, 0.38 ml) was gradually added at 20° C. The solution was stirred 10 min at room temperature and then it was poured into ice-cold water and extracted with ethyl acetate. The organic extracts were combined, dried and evaporated to dryness. The residue was recrystallized from acetic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25]Br>>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: CC(=O)NCc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Fc1ccccc1CCBr
Product: CC(=O)NCc1ccc2c(c1)N(C1CCN(CCc3ccccc3F)CC1)CC2
Yield: 52.5 %

Procedure:
1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and 2-fluorophenethyl bromide (220 mg) were treated as in Example 2 to give the title compound (190 mg) as a whitepowder (yield: 52%).
Reaction SMILES: [C:1](OC1C2C(=CC=C(C)C=2)N(CC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[C:28]1=[O:37])[CH:24]([CH3:26])[CH3:25]>>[C:1]([O:36][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:28]1=[O:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: CC(C)CN1C(=O)C(=O)c2ccccc21
Product: CC(C)CN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate from 1-isobutylindoline-2,3-dione. 1H-NMR δ 8.10 (d, 2H), 7.59 (t, 1H), 7.46 (m, 3H), 7.34 (m, 1H), 7.05 (t, 1H), 6.89 (d, 1H), 6.18 (s, 1H), 3.52 (m, 2H), 2.18 (m, 1H), 1.01 (dd, 6H).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[CH3:17]I>CO>[CH3:17][N:8]1[C:3](=[O:2])[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7]1
Reactant: CI
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cn1
Solvent: CO
Product: Cn1cc(NC(=O)OC(C)(C)C)ccc1=O
Temperature: 25 °C

Procedure:
To a stirred solution of tert-butyl 6-methoxypyridin-3-ylcarbamate (14.4 g, 64.2 mmol) in MeOH (95 mL) was added methyl iodide (14.6 g, 103 mmol). The reaction mixture was heated at reflux for 16 h, cooled to RT and concentrated down. The residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[N:15]([Sn](C)(C)C)=[N+:16]=[N-:17]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:17][N:16]=[N:15][N:2]=2)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2nnn[nH]2)ccc1OC
Temperature: 25 °C

Procedure:
A stirred solution of methyl 5-cyano-2-methoxybenzoate (0.87 g, 4.5 mmol) in toluene (4 mL) was treated with azidotrimethyltin (1.85 g, 9.0 mmol) and heated at reflux overnight. After cooling to room temperature, the solvents were evaporated. The crude product was dissolved in ethyl acetate, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% methanol/methylene chloride) afforded 0.78 g (75%). LC/MS (HPLC method 3): tR=1.66 min, 235.05 (MH)+.
Reaction SMILES: O[NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[CH2:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH2:4]1>C(O)(=O)C.[Zn]>[NH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[CH2:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH2:4]1
Reactant: C=C1c2ccccc2CC(NO)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: C=C1c2ccccc2CC(N)c2ccccc21
Reaction time: 2 h

Procedure:
To a stirred slurry of zinc dust (0.9 g, 0.138 mole) in 100 ml of glacial acetic acid stirred in an oil bath at 65° was added 10-hydroxyamino-5-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (10 g, 42 mmole). The mixture was stirred in the oil bath for 2 hours, cooled, and quenched in 500 ml of water. The mixture was made basic with concentrated ammonia, then extracted with ether. The combined ether layers were washed with water, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was recrystallized from hexane to give 7.8 g, m.p. 84.5°-86.5°.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:41])[NH:19][CH2:20][C:21]([N:23]2[CH:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:33][CH2:32][CH:24]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>[Pd].C(O)C>[C:28]([O:27][C:25]([CH:24]1[CH2:32][CH2:33][CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23]1[C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:41])[NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 83 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 100, but starting from 10.2 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-benzyloxycarbonylphenyl)-ureido]acetyl}-5-phenylprolinate and 1 g of 5% palladium on charcoal in 300 cm3 of ethanol. After treatment, 7.1 g of (2RS,5RS)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 236° C., are obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[NH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[N:4]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Clc1ncc2c(Br)c[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCn1cc(Br)c2cnc(Cl)nc21
Temperature: 100 °C

Procedure:
A suspension of 5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.43 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (173 mg, 0.65 mmol) and K2CO3 (119 mg, 0.86 mmol) in a mixture of DMSO and THF (8.0 mL, 1:3, v/v) was heated at 100° C. under microwave irradiation for 30 min. The mixture was diluted with ethyl acetate (35 mL), washed with water (3×) and concentrated to provide the crude 2-(3-(5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propyl)isoindoline-1,3-dione (MS m/z 420.05 [M+H]+) which was used in next step without further purification.
Reaction SMILES: [OH:1]NC(=N)CC.C(C1N=C(C(C(NC(C(N[C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])CS(CC2C=CC=CC=2)(=O)=O)=O)CC)=O)ON=1)C>>[N:37]1([C:35]([OH:36])=[O:1])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: CCC(=N)NO
Reactant: CCc1noc(C(=O)C(CC)NC(=O)C(CS(=O)(=O)Cc2ccccc2)NC(=O)N2CCOCC2)n1
Product: O=C(O)N1CCOCC1

Procedure:
By proceeding in a similar manner to that described in Example 20 above but using N-hydroxy-propionamidine instead of N-hydroxy-benzamidine in step 1, there was prepared morpholine-4-carboxylic acid {1-[1-(3-ethyl-[1,2,4]oxadiazole-5-carbonyl)-propylcarbamoyl]-2-phenylmethanesulfonyl-ethyl}-amide. 1H NMR (DMSO): 8.73 (d, J=6.4 Hz, 1H), 7.40–7.33 (m, 5H), 7.01 (d, J=8 Hz, 1H), 4.88–4.82 (m, 1H), 4.71–4.65 (m, 1H), 4.47 (s, 2H), 3.57–3.24 (m, 10H), 2.81 (q, J=7.6 Hz, 2H), 1.99–1.88 (m, 1H), 1.75–1.64 (m, 1H), 1.26 (t, J=7.6 Hz, 3H), 0.92 (t, J=7.6 Hz, 3H). MS: (M++1) 522.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[F:12])=O.[NH2:13][C:14]([NH2:16])=[O:15].[OH-].[Na+]>CC#N>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]([NH2:16])[O:15][CH:2]=2)=[C:6]([F:12])[CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1F
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1nc(-c2ccc(Br)cc2F)co1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 2-bromo-1-(4-bromo-2-fluorophenyl)ethanone (53 mg, 0.18 mmol) and urea (10.6 mg, 0.18 mmol) in CH3CN (0.7 mL) was heated at 80° Celsius for 18 hours. The mixture was cooled to rt and made basic with NaOH (2 N). The resulting solution was extracted with EtOAc and the extract was dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified using FCC to give 4-(4-bromo-2-fluorophenyl)oxazol-2-amine (37 mg, 82%). MS (ESI): mass calcd. for C9H6BrFN2O, 255.96; m/z found, 257.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.78 (m, 1H), 7.58 (d, J=4.3, 1H), 7.36-7.32 (m, 1H), 7.28 (dd, J=10.5, 1.9, 1H), 4.60 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][CH2:14][CH2:13]2)=[O:11])=[C:7]([NH:20]C(=O)OCC2C=CC=CC=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:20][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[NH:9][C:8]=1[C:10]([N:12]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)c1cc(NC(=O)OCc2ccccc2)c(C(=O)N2CCNC(=O)CC2)[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(N)c(C(=O)N2CCNC(=O)CC2)[nH]1
Reaction time: 18 h
Yield: 74.1 %

Procedure:
A mixture of the previously benzyl 5-tert-butyl-2-(5-oxo-1,4-diazepane-1-carbonyl)-1H-pyrrol-3-ylcarbamate (40 mg, 0.097 mmol), Pd on charcoal (10% w/w, 20 mg) and methanol (2 mL) was shaken in a Parr shaker under hydrogen (50 psi) for 18 hours. The reaction mixture was filtered through celite and the residue was concentrated under vacuum to afford 20 mg of the desired 1-(4-amino-2-tert-butyl-1H-pyrrole-5-carbonyl)-1,4-diazepan-5-one as a clear oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[NH:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:29]C1C=C(C2C=C(C(O)=O)NN=2)C=CC=1>>[ClH:2].[Cl:29][C:8]1[CH:7]=[C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:21][CH:22]=3)=[O:15])[NH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)n[nH]1
Reactant: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2ccc(Cl)cc2)n[nH]1
Agent: Cl
Product: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2cccc(Cl)c2)n[nH]1

Procedure:
The title compound was prepared in analogy to Example 1 using (R)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (prepared in Example 12) instead of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate and 3-(3-chlorophenyl)-1H-pyrazole-5-carboxylic acid (CAS-595610-50-7) instead of 3-phenyl-1H-pyrazole-5-carboxylic acid. White solid. MS (ISP): 383.1 ([M+H]+).
Reaction SMILES: [K+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])=[CH:5][CH:4]=1.[CH3:16]I.O>CN(C)C=O>[CH3:16][O:13][C:12](=[O:14])[C:11](=[O:15])[CH:10]=[CH:9][C:6]1[CH:5]=[CH:4][C:3]([Br:2])=[CH:8][CH:7]=1
Reactant: CI
Reactant: O=C([O-])C(=O)C=Cc1ccc(Br)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(=O)C=Cc1ccc(Br)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 30.6 %

Procedure:
A mixture of 4-(4-bromo-phenyl)-2-oxo-3-butenoic acid potassium salt (48.0 g, 164.0 mmol) prepared in Step 1 and methyl iodide (20.0 mL, 327.0 mmol) in N,N-dimethylformamide (250.0 mL) was stirred at 75° C. for 4 hours and then distilled water was added thereto. The reaction mixture was extracted with ethyl acetate. The extract was washed with a sodium hydrogen carbonate solution and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 13.5 g of the titled compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:28][CH3:29])[CH2:15][CH2:16][N:17]([CH3:27])[C:18]([C:20]1[NH:21][C:22]([CH:25]=O)=[CH:23][CH:24]=1)=[O:19])[CH3:13]>>[CH2:28]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][N:17]([CH3:27])[C:18]([C:20]1[NH:21][C:22]([CH:25]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[CH:23][CH:24]=1)=[O:19])[CH3:29]
Reactant: CCN(CC)CCN(C)C(=O)c1ccc(C=O)[nH]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCN(C)C(=O)c1ccc(C=C2C(=O)Nc3ccc(Br)cc32)[nH]1
Yield: 55 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (212 mg, 1 mmol) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-diethylaminoethyl)methylamide to give 246 mg (55%) of the title compound.