Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:24][C:25]1[N:26]([CH2:34][CH2:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH:27]=[C:28]([Sn](C)(C)C)[N:29]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:28]5[N:29]=[C:25]([CH3:24])[N:26]([CH2:34][CH2:35][O:36][CH:37]6[CH2:42][CH2:41][CH2:40][CH2:39][O:38]6)[CH:27]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc([Sn](C)(C)C)cn1CCOC1CCCCO1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CCOC1CCCCO1
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 32.3 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), 2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethylstannyl)-1H-imidazole (600 mg, 1.6 mmol) in dioxane (2 ml) was bubbled with N2 for about 2 min and then stirred at 120° C. for 35 min under the irradiation of microwave. Filtered, concentrated and purified by pre-TLC (EtOAc) to give 130 mg of 256. Yield=32%. 1H NMR (CDCl3, 400 MHz): δ8.44-8.42 (m, 1H, ArH), 7.81 (s, 1H), 7.58 (s, 1H), 7.48-7.46 (m, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.19 (s, 1H), 4.51-4.95 (m, 1H), 4.45-4.44 (t, 1H), 4.39-4.38 (m, 2H), 4.38-4.37 (m, 2H), 4.07-4.04 (m, 2H), 4.00-4.97 (m, 1H), 3.63-3.54 (m, 2H), 3.40-3.36 (m, 1H), 2.49 (s, 3H), 1.76-1.60 (m, 4H), 1.48-1.47 (m, 2H) LC-MS: m/z=504 [M+H+]
Reaction SMILES: C(O)(=O)CC.[NH4+:6].[OH-].[CH3:8][C:9]1[C:14](NC(=O)CC)=[C:13]([CH3:20])[N:12]=[C:11]([NH:21][C:22](=O)[CH2:23][CH3:24])[CH:10]=1>>[CH3:20][C:13]1[N:12]=[C:11]2[N:21]=[C:22]([CH2:23][CH3:24])[NH:6][C:10]2=[C:9]([CH3:8])[CH:14]=1
Reactant: CCC(=O)Nc1cc(C)c(NC(=O)CC)c(C)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCC(=O)O
Product: CCc1nc2nc(C)cc(C)c2[nH]1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of 8.44 g of a 55:45 mixture of 2-Amino-3-nitro-4,6-dimethylpyridine and 2-Amino-4,6-dimethyl-5-nitropyridine in MeOH (1.2 L) was added 10% Pd/C (2.4 g). The reaction vessel was evacuated then purged with H2 at 1 atm. and stirred vigorously for 18 hours. Filtration (celite), and concentration gave 6.65 g of a mixture of 2,3-diamino-4,6-dimethylpyridine and 2,5-diamino-4,6-dimethylpyridine as a dark solid. To 5.40 g (39.4 mmol) of this mixture was added propionic acid (8.80 mL, 118 mmol) followed by polyphosphoric acid (100 mL). This stirred mixture was heated to 90° C. for 3 hours then to 100° C. for 1 hour. After the reaction was complete, the warm mixture was poured onto 300 g of ice and the mixture was made basic with NH4OH. The mixture was extracted (4×50 mL CH2Cl2), dried (K2CO3) and concentrated to give a mixture of the title compound and 4,6-dimethyl-2,5-bis(propionamido)pyridine. Purification (SiO2, 5% MeOH/EtOAc) gave 1.66 g of the title compound as the slower eluting component.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:31])[CH2:16][N:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O:32]([C@H:40]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:41][CH:42]=[O:43])[Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].S([O-])(O)(=O)=O.[K+]>C1COCC1.CCCCCC>[CH2:24]([N:17]([CH:16]([CH:42]([OH:43])[CH2:41][C@H:40]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:15]([O:14][CH3:13])=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CN(Cc1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCC[C@H](CC=O)O[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@H](CC(O)C(C(=O)OC)N(Cc1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: -75 °C
Yield: 7.9 %

Procedure:
A solution of 0.5 ml of diisopropylamine in 15 ml of THF was treated at 0° C. with 2.0 ml of a solution of 1.6M n-butyllithium in hexane and, after stirring, cooled to -75° C. Then, a solution of 765 mg of N-benzyl-N-phenylglycine methyl ester in 3 ml of THF was added. After stirring a solution of 700 mg of (R)-3-(t-butyl-dimethylsiloxy)tetradecanal (Example Bb)) in 5 ml of THF was added dropwise. After stirring at -75° C. the reaction mixture was poured into aqueous potassium hydrogen sulphate and extracted with ether. The ether phase was dried, concentrated, partitioned between hexane and methanol/water (7:3), the hexane phase was dried and concentrated and the residue was chromatographed on silica gel with pentane/ether (5:1). There were obtained 96.3 mg of methyl (5R)-2-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate, diastereomer A, MS: 540 (M+ ·-C4H9 ·), and 142.8 mg of methyl (5R)-2-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate, diastereomer B, MS: 540 (M+ ·-C4H9 ·), and 313.4 g of a mixture of the above two diastereomers.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:6][O:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].[CH3:32][C:33](C)=O>>[C:30]([O:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:21])[C:5]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]#[C:32][CH3:33])=[CH:15][CH:14]=3)=[CH:6][O:7]2)=[CH:2][CH:11]=1)#[C:29][CH3:28]
Reactant: C#CCBr
Reactant: COc1ccc(-c2coc3cc(O)cc(O)c3c2=O)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC#COc1ccc(-c2coc3cc(OC#CC)ccc3c2=O)cc1

Procedure:
A mixture of 5,7-dihydroxy-4′-methoxyisoflavone (2.54 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.72 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.31 g of a product with the following characteristics: m.p. 162-163° C.; 1H NMR (CDCl3) δ: 2.44 (m, 1H, CH), 2.57 (m, 1H), 4.54 (s, 2H), 4.56 (s, 2H), 6.85-8.08 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1C
Product: CN1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1

Procedure:
In the same manner as described in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-methylpiperazine, and xylene was refluxed for 3 hours to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 254°-255° C.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)N)#[N:3].N([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>C(O)(=O)C.O>[C:2]([C:4]1[CH:5]=[C:6]([S:15]([Cl:1])(=[O:17])=[O:16])[CH:8]=[CH:9][CH:10]=1)#[N:3]
Reactant: N#Cc1cccc(N)c1
Reactant: O=S=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixed solution of 200 ml of water and 250 ml of concentrated hydrochloric acid was added 25.0 g (212 mmol) of 3-cyanoaniline followed by stirring. An aqueous solution (80 ml) of 15.5 g (223 mmol) of sodium nitrite was added dropwise thereinto at −10° C. The reaction solution was added to acetic acid saturated with sulfur dioxide (prepared by saturating sulfur dioxide in 250 ml of acetic acid followed by adding 2.1 g of cuprous chloride) under ice-cooling and stirring. After 1 hour, the reaction solution was poured onto 500 ml of ice water and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and brine successively, and dried over magnesium sulfate. The solvent was evaporated, a mixed solution of diethyl ether and hexane was added to the residue and the crystals were collected by filtration to give 16.0 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]([N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])=[O:10].C(N(CC)CC)C>O1CCCC1.O>[C:2]1([NH:1][C:9]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCNC1=O
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1NCCN1C(=O)Nc1ccccc1
Reaction time: 1 h

Procedure:
10.2 parts by weight of aniline were first introduced into 120 parts by volume of 80% strength aqueous tetrahydrofurane at pH = 8 and 14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one were added in portions at room temperature while stirring and keeping the pH value at 7-8 by simultaneous addition of triethylamine. The mixture was further stirred until the pH was constant, 80 parts by volume of water were added, the tetrahydrofurane was stripped off in vacuo, the pH was adjusted to 2.5 and after standing for one hour in an ice bath the product which had precipitated was filtered off. It was washed with ice water and dried over P2O5 in a vacuum desiccator.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([O:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]=[C:26]3[CH3:50])=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1>O.C(OCC)(=O)C>[CH:13]1([O:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:37][CH:38]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]=[C:26]3[CH3:50])=[CH:23][CH:24]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CCCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.70 g), sodium hydrogen carbonate (2.62 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(cyclopentyloxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.96 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.41 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.78 g, 66%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([CH2:15][OH:16])[CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CCCCC.C1COCC1.C(OCC)(=O)C>[CH2:3]([O:10][CH2:11][CH:12]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC(CO)COCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
NaH (0.87 g, 80% dispersion in oil, 29.1 mmol) was washed three times with dry pentane, dried in vacuo, and then suspended in 60 mL of dry THF. A solution of 2-benzyloxymethyl-1,3-propanediol (5.70 g, 29.1 mmol) in 5 mL of THF was next added dropwise over 20 min. and the reaction mixture stirred at room temperature for 1.5 hrs. to give a white slurry. t-Butyldimethylsilylchloride (4.38 g, 29.1 mmol) was then added portionwise over 3 min. and the reaction mixture stirred at room temperature for 2 hours further. The mixture was next diluted with 150 mL of ethyl acetate and washed with 10% aqueous potassium carbonate and brine, dried over MgSO4, filtered, and concentrated to give a colorless oil. Purification by column chromatography on silica gel (ethyl acetate/hexanes) provided 7.41 g (82%) of 2-benzyloxymethyl-3-t-butyldimethylsiloxy-1-propanol as a clear, colorless liquid.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[C:4]([O:6][CH3:7])=[O:5].C([Cl:13])(=O)C.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>II>[Cl-:13].[CH3:1][O:2][CH:3]([P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(OC)OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: II
Product: COC(=O)C(OC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 55 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
25 g (0.186 mol) of methyl dimethoxyacetate are added to 27 ml (0.215 mol) of acetyl chloride at ambient temperature. 0.1 g (0.2 mol %) of diiodine are added and then the reaction mixture is stirred at 55° C. for 16 hours. The excess acetyl chloride is evaporated under vacuum and then the residue is dissolved in 100 ml of dichloromethane. 49 g (0.204 mol) of triphenylphosphine are added and then the reaction mixture is stirred at 37° C. for 3 hours. The solvents are evaporated and then the residue is crystallized from diisopropyl ether. 70 g of (methoxy(methoxycarbonyl)methyl)triphenylphosphonium chloride are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][N+:15]([O-:17])=[O:16].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]([F:12])([F:11])[F:10])=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])C=C(c1ccc(Br)cc1)C(F)(F)F

Procedure:
A stirred solution of 4′-bromo-2,2,2-trifluoroacetophenone (0.392 g, 2.00 mmol) and CH3NO2 (0.488 g, 8.0 mmol) in dry toluene (70 mL) containing N,N-diethylenediamine (30 mmol) is heated at reflux with a Dean and Stark trap until complete removal of H2O. The cooled solution is washed with 5% aqueous HCl, dried over MgSO4, filtered, evaporated in vacuo and the resulting residue when purified by chromatography gives the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:22])[CH:16]=[C:17]([NH2:21])[O:18][CH2:19][CH3:20])[CH3:13]>C(O)(C)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:16]([C:15]([O:14][CH2:12][CH3:13])=[O:22])[C:17]([O:18][CH2:19][CH3:20])=[N:21][C:17]=1[NH2:21])=[O:22])[CH3:13]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
Upon heating a solution of 7.6 g of 3-nitrobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of isopropanol for 6 hours, 2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 129° (isopropanol) is obtained.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5]>O>[C:4]1(=[O:6])[O:8][CH2:1][CH2:2][CH2:3]1.[CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][OH:5]
Reactant: O=C(O)/C=C\C(=O)O
Solvent: O
Product: O=C1CCCO1
Product: OCCCCO
Temperature: 170 °C
Reaction time: 1.92 h

Procedure:
0.5g of the catalyst of Example 14, and then 50g of a 20 weight percent solution of maleic acid in water, were placed in the glass liner of a 300 ml autoclave, which was then sealed, purged several times with hydrogen and then pressurized with hydrogen to 1100 psig. The autoclave was heated to 170° C. and the pressure adjusted to 1850 psig. As the reaction proceeded, additional hydrogen was added when the pressure dropped 50 to 100 psi to bring the pressure back to or near the original pressure at reaction temperature. The reaction was effected for 115 minutes, the reactor and contents cooled to room temperature, and the gas volume measured. The gases were analyzed by gas chromatography. The liquid phase was also analyzed by gas chromatography after filtering out the solids. The conversion of maleic acid was 100 percent, and the yields of γ-butyrolactone and 1,4-butanediol were 50.0% and 19.0%, respectively.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:52][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.CCOC(C)=O>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3nn(Cc4ccccc4)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 200 mg (0.30 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 5 mL of DMF is added 0.45 mL (0.45 mmol, 1.5 equiv) of a 1.0M solution of NaN(TMS)2. The resulting solution is stirred 5 min, then 76 mg (0.54 mmol, 1.8 equiv) of methyl iodide is added. The resulting solution is stirred at RT for 1 h then heated to 50° C. for 16 h. The solution is cooled to RT, poured into 40 mL of EtOAc and extracted with H2O (1×40 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the resulting material by silica gel flash chromatography with hexane/ethyl acetate 3/2 as eluent gave 127 mg of the title compound as an off-white solid, contaminated with starting material, which is inseparable, in a ratio of approximately 1/1: 1H NMR (300 MHz, CDCl3) δ7.86 (d, 1H, J=8.1), 7.33-6.88 (m, 21H), 5.58 (s, 2H), 5.43 (s, 2H), 5.05 (m, 1H), 5.00 (m, 1H), 4.50 (d, 1H), 4.25 (m, 3H), 3.85 (s, 3H), 3.58 (dd, 1H, J=5.1, 16.0), 1. 59 (s, 3H), 1.06 (2×d, 6H, J=6.6); Rf =0.15 in hexane/ethyl acetate 2/1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]4[CH2:23][CH2:22]4)[C:13]3=[O:24])[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]2=[N:6][CH:7]=1.[O:30]1CC[O:32][BH:31]1.C([O-])(=O)C.[K+].Cl>O1CCOCC1.CO.O>[CH:21]1([N:14]2[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:12]([CH2:11][C:9]3[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]4=[N:6][CH:7]=[C:2]([B:31]([OH:32])[OH:30])[CH:3]=[C:4]4[N:10]=3)[C:13]2=[O:24])[CH2:23][CH2:22]1
Reactant: B1OCCO1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(Br)cnc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(B(O)O)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The mixture of compound 16 (0.5 g, 1 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (0.382 g, 1.5 mmol) and potassium acetate (0.16 g, 1.6 mmol) in dioxane (20 mL) under argon atmosphere was stirred at room temperature for 10 minutes. To the resulting mixture dichloro(diphenylphosphinoferrocene)palladium (39 mg, 0.05 mmol) was added. The resulting mixture was warmed to 115° C. for 3 hours. The mixture was allowed to cool down to room temperature then the solvent was removed. The residue (23-1) was dissolved in acetonitrile (40 mL) and an aqueous solution of hydrochloric acid 6 M (1.7 mL, 10 mmol) was added. The resulting mixture was stirred at 110° C. for 2 hours. The mixture was allowed to cool down to room temperature and water (30 mL) was added the pH was adjusted to pH=7 by addition of a solution 7N of ammoniac in methanol. The resulting mixture was concentrated and the residue was purified by preparative HPLC. The title compound 23 was isolated as a white solid (309 mg, 67%). m/z=421 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl.O1CCOCC1.CCN(CC)CC>COCCO>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[C:3]([O:14][CH3:15])=[CH:4][C:5]3[CH2:11][NH:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:18][CH:19]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)NC(=O)CNC2
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)NC(=O)CNC2
Temperature: 120 °C
Yield: 9.8 %

Procedure:
To a solution of 8-amino-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (66 mg, 0.32 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (100 mg, 0.30 mmol) in 2-methoxyethanol (3 mL) was added 4N HCl-dioxane (50 uL). The mixture was heated under microwave irradiation to 120° C. for 20 minutes. The mixture was adjusted to pH 9 (Et3N) and purified by flash chromatography on silica get (MeOH-DCM) to give 15 mg (9%) of N-{(1R,2R)-2-[5-chloro-2-(7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a mustard yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.47 (s, 1H), 6.73 (s, 1H), 5.57 (d, J=7 Hz, 1H), 5.46 (d, J=7 Hz, 1H), 4.00 (s, 2H), 3.92 (s, 3H), 3.61 (s, 2H), 3.29 (m, 1H), 2.89 (s, 3H), 2.21 (m, 2H), 1.83 (m, 2H), 1.65 (m, 1H), 1.38 (m, 2H), 1.25 (m, 2H); MS (m/e) 510 (M+1); mp 135° C. (dec.).