Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[H-].[Na+].[CH3:30][C:31]1[O:35][C:34]([C:36](=[O:39])[CH2:37]Br)=[CH:33][CH:32]=1>O1CCCC1>[CH3:30][C:31]1[O:35][C:34]([C:36]([CH2:37][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[CH2:4][CH:3]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]2=[O:1])=[O:39])=[CH:33][CH:32]=1
Reactant: Cc1ccc(C(=O)CBr)o1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccc(C)o1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrabydro-2H-1,5-benzodiazepine (1.0 g) obtained from Step 1 of Example 89 was dissolved in tetrahydrofuran (10 ml), under argon atmosphere 60% sodium hydride (0.16 g) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, a solution of 5-methyl-2-bromoacetylfuran (1.23 g) in tetrahydrofuran (1 ml) was added to the mixture, stirred at room temperature for 30 minutes. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1), to thereby obtain 0.89 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=O.Cl.[NH:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1)[NH2:19]>C(O)C>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([N:18]2[C:5]([C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=3)=[CH:4][C:3]([C:2]([F:16])([F:15])[F:1])=[N:19]2)=[N:21][CH:22]=1)(=[O:27])=[O:28]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)nc1
Yield: 53.7 %

Procedure:
4,4,4-Trifluoro-1-(4-bromophenyl)1,3-butanedione (600 mg) (prepared according to the method of Thomas D. Penning, et al.; J. Med. Chem., 1997, 40, 1347-1365.) and 2-hydrazino-5-(methylsulfonyl)pyridine hydrochloride (420 mg) were mixed in ethanol (40 mL), and the resulting solution was refluxed for 3 days. Upon cooling, white precipitates came out. The white precipitates were collected by filtration and purified by flash chromatography using 70:30 of methylene chloride and hexane to give the title compound (450 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:5]=2[N:4]([CH2:14][CH2:15][O:16]C2CCCCO2)[C:3]1=[O:23].Cl.[OH-].[Na+]>O>[OH:16][CH2:15][CH2:14][N:4]1[C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][C:6]=2[C:7](=[O:8])[N:2]([CH3:1])[C:3]1=[O:23]
Reactant: CN1CCc2c(c(=O)n(C)c(=O)n2CCOC2CCCCO2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2c(c(=O)n(C)c(=O)n2CCO)C1

Procedure:
3 g of 3,6-dimethyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione were dissolved in 150 ml of water and the pH was adjusted to 1 with conc. hydrochloric acid at 20°-25° C., with stirring. After stirring for 5 h at room temperature, 2 N sodium hydroxide solution was added dropwise to pH 8 and the reaction mixture was concentrated under reduced pressure. After azeotropic drying with ethanol, the residue was purified by chromatography on silica gel in a medium-pressure column with dichloromethane/methanol (volume ratio 85:15) and by recrystallization from dichloromethane/diethyl ether.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15]C(Cl)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:19][C@H:20]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@H:22]([CH2:23][C@@H:24]([OH:47])[C@@H:25]3[C@@H:40]2[CH2:39][C@H:38]([OH:45])[C@@:37]2([CH3:46])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C@H:30]([CH3:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21]1.O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][NH:19][C@H:20]3[CH2:43][CH2:42][C@@:41]4([CH3:44])[C@H:22]([CH2:23][C@@H:24]([OH:47])[C@@H:25]5[C@@H:40]4[CH2:39][C@H:38]([OH:45])[C@@:37]4([CH3:46])[C@H:26]5[CH2:27][CH2:28][C@@H:29]4[C@H:30]([CH3:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](NOCC5c6ccccc6-c6ccccc65)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 0 °C
Yield: 71 %

Procedure:
A solution of 9-fluorenylmethoxycarbonyl chloride (1.4 g; 5.4 mmol) in 1,4-dioxane (18 mL) was added dropwise to a suspension of (3β,5β,7α,12α)-3-amino-7,12-dihydroxycholan-24-oic acid A (2.0 g; 4.9 mmol) (3) in 10% aq. Na2CO3 (30 mL) and 1,4-dioxane (18 mL) stirred at 0° C. After 6 h stirring at room temperature H2O (100 mL) was added, the aqueous phase washed with Et2O (2×90 mL) and then 2 M HCl (15 mL) was added (final pH: 1.5). The precipitated solid was filtered, washed with H2O (3×100 mL), vacuum dried and then purified by flash chromatography to give B as a white solid (2.2 g; 3.5 mmol). Yield 71%.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][CH2:6][C:5]([NH:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:4]1.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.Cl[Cu]>[NH2:13][C:12]1[C:11]2[C:10]([N:9]=[C:5]3[C:4]=1[C:3](=[O:2])[CH2:8][CH2:7][CH2:6]3)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: N#Cc1ccccc1NC1=CC(=O)CCC1
Agent: Cl[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Nc1c2c(nc3ccccc13)CCCC2=O
Yield: 41.4 %

Procedure:
In 2 liters of tetrahydrofuran were combined 219.3 g of 2-(3-oxocyclohexen-1-yl)aminobenzonitrile hydrochloride, 250 g (2 eq) of milled K2CO3, and 3 g of CuCl catalyst. The mechanically stirred mixture was refluxed 5 hours and then filtered hot to remove the inorganic salts. The filtrate was evaporated to a residue and the residue was recrystallized twice from isopropanol to yield 77.4 g (41%) of a powder, melting point 236°-238° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].[I-].[K+]>CO.O>[Cl:20][CH2:19][CH2:18][CH2:17][CH2:16][N:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]1=[O:1]
Reactant: ClCCCCBr
Reactant: Cc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccn(CCCCCl)c(=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.8 %

Procedure:
A mixture of 2-hydroxy-4-methylpyridine (1.50 g, 13.75 mmol) and potassium carbonate (1.90 g, 13.75 mmol) in 13 ml of methanol were stirred at room temperature for 15 minutes and then 1-bromo-4-chlorobutane (3.54 g, 20.62 mmol) and a spatula tip of potassium iodide were added thereto. The reaction mixture was heated to reflux for 6 hours and then stirred at room temperature for 12 hours. Water was then added to the reaction mixture, and the aqueous mixture was extracted with dichloromethane. Drying of the organic phase and removal of the desiccant by filtration was followed by concentration of the organic phase in vacuo. Flash chromatography of resulting residue on silica gel (eluent: CH2Cl2/CH3OH: 98:2) afforded 2.0 g of 1-(4-chlorobutyl)-4-methylpyridin-2(1H)-one.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[N:11]([CH2:14][CH:15]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)[N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[N+]=[N-]>C(OCC)C>[CH2:19]([N:16]([CH2:17][CH3:18])[CH:15]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)[CH2:14][NH2:11])[CH3:20]
Reactant: CCN(CC)C(CN=[N+]=[N-])c1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCN(CC)C(CN)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
To a suspension of 0.76 g (0.02 mol) of lithium aluminum hydride in 100 mL of dry diethyl ether under a nitrogen atmosphere and cooled to -10° to 0° C. add carefully in portions 10.67 g (0.08 mol) of aluminum chloride. When the initial reaction has ceased add dropwise a solution of 2.68 g (0.01 mol) of α-azidomethyl-N,N-diethyl-1-naphthalenemethanamine in 50 mL of diethylether. When the addition is complete allow the reaction mixture to warm to room temperature. Follow the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction carefully quench the excess reducing agent by the addition of sodium sulfate decahydrate. Filter the solids and wash the solids with 500 mL of hot methylene chloride. Dry the filtrate over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:34])[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][C:16]3([NH:22]C(=O)C4C=CC=CC=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:10][C:9]2([CH3:33])[CH3:32])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:22][C:16]1([CH2:15][C:14]([N:11]2[CH2:12][CH2:13][C@@:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([OH:34])[C:9]([CH3:33])([CH3:32])[CH2:10]2)=[O:31])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC1(C)CN(C(=O)CC2(NC(=O)c3ccccc3)CCOCC2)CC[C@]1(O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CN(C(=O)CC2(N)CCOCC2)CC[C@]1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.3 %

Procedure:
To (S)-tert-butyl 4-(2-(4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-2-oxoethyl)tetrahydro-2H-pyran-4-ylcarbamate (from step 3, 0.17 g, 0.35 mmol) was added 4.0N HCl in dioxane (2 mL) at room temperature. Upon completion of addition, the reaction mixture was stirred at room temperature for 24 h. At the conclusion of this period, the reaction mixture was concentrated under reduced pressure and then partitioned between ethyl acetate (20 mL) and 1N NaOH (10 mL). The ethyl acetate layer was separated, washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (0.135 g) as a foamy solid. MS (ESI+)=381.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[CH:9]1([N:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C@H:22]3[CH2:26][C@H:25]([OH:27])[CH2:24][N:23]3[C:28](=[O:30])[CH3:29])=[O:21])[CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10]1>>[CH:9]1([N:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C@H:22]3[CH2:26][C@H:25]([O:27][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH2:24][N:23]3[C:28](=[O:30])[CH3:29])=[O:21])[CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10]1
Reactant: Fc1cccc(I)c1
Reactant: CC(=O)N1C[C@@H](O)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1
Product: CC(=O)N1C[C@@H](Oc2cccc(F)c2)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1

Procedure:
The title compound was prepared by Preparation 1: acylation as described for Example 114; or Preparation 2: reaction of 3-fluoro-iodobenzene and (2R,4S)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidin-1-yl]-ethanone as described for Example 48. MS (ESI): mass calcd. for C22H30FN3O3, 403.23; m/z found, 404.3 [M+H]+. 1H NMR (CDCl3): 7.28-7.23 (m, 1H), 6.75-6.69 (m, 1H), 6.69-6.64 (m, 1H), 6.65-6.55 (m, 1H), 5.15-4.90 (m, 1H), 4.07 (dd, J=11.2, 4.9 Hz, 1H), 3.89-3.47 (m, 5H), 3.01-2.83 (m, 1H), 2.74-2.27 (m, 6H), 2.13-2.00 (m, 6H), 1.95-1.65 (m, 6H).
Reaction SMILES: CN1CCCC1=O.C(N(C(C)C)CC)(C)C.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:26])=[CH:20][CH:19]=1.Cl[C:37]1[C:46]2[C:41](=[CH:42][C:43]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[C:44]([C:47]#[N:48])[CH:45]=2)[N:40]=[CH:39][CH:38]=1>C(OCC)(=O)C.O1CCCC1>[C:47]([C:44]1[CH:45]=[C:46]2[C:41](=[CH:42][C:43]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[N:40]=[CH:39][CH:38]=[C:37]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:26])=[CH:20][CH:19]=1)#[N:48]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: COc1ccc(NC(=O)Nc2ccc(O)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCc5ccccc5)c(C#N)cc34)cc2)cc1
Temperature: 130 °C
Yield: 43.5 %

Procedure:
After adding 1-methylpyrrolidone (3.4 ml) and diisopropylethylamine (3.6 ml, 20.78 mmol) to N-(4-hydroxyphenyl)-N′-(4-methoxyphenyl)urea (4.25 g, 16.46 mmol), the mixture was heated and stirred at 130° C. to complete dissolution, and then 4-chloro-6-cyano-7-benzyloxyquinoline (5.10 g, 17.32 mmol) was added and the mixture was stirred at 130° C. for 1.5 hours and at 150° C. for 1 hour. Upon addition of diisopropylethylamine (1.2 ml, 6.93 mmol), the mixture was further stirred for 1 hour. After cooling and adding tetrahydrofuran and ethyl acetate, the mixture was washed with saturated sodium bicarnobate water and saturated brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtain crystals were washed with diethyl ether/hexane, acetonitrile/diethyl ether/hexane, methanol and dimethylsulfoxide/water, in that order. The obtained crystals were dissolved in tetrahydrofuran, filtered with silica gel (200 cc silica gel) and flushed with 3000 ml of tetrahydrofuran, and the solvent was distilled off under reduced pressure. The crystals were then washed with diethyl ether, acetonitrile and diethyl ether:ethanol=5:1 and dried by aspiration to obtain the title compound (3.70 g, 7.1627 mmol, 43.52%) as brown crystals.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)[CH:10]=[CH:11][CH:12]=1.FC(F)(F)C(O)=O>ClCCl>[N:20]1[CH:19]=[CH:18][N:17]=[C:16]2[NH:21][C:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[CH:2]=[O:1])=[CH:14][C:15]=12
Reactant: c1cc(-c2cc3nccnc3[nH]2)cc(C2OCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cccc(-c2cc3nccnc3[nH]2)c1
Yield: 47.3 %

Procedure:
A solution of 6-(3-[1,3]dioxan-2-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazine [1.6 g, Example 1(g)] in dichloromethane (50 mL) was treated with trifluoroacetic acid (5 mL). The resultant mixture was heated at reflux for 6 hours, then allowed to cool overnight and then evaporated. The residue was triturated with diethyl ether to give a yellow solid which was recrystallised from ethyl acetate to give the title compound (0.6 g) as a yellow crystalline solid, m.p. 268–270° C. [Elemental analysis: C, 69.96; H, 3.92; N,18.69%. Calculated for C13H9N3O: C, 69.95; H, 4.06; N, 18.82%]
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](=[O:40])[CH2:38][CH3:39])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([CH2:36][C:37](=[O:40])[CH2:38][CH3:39])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: CCC(=O)Cc1ccc(O)cc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CCC(=O)Cc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol (4-hydroxyphenyl)butanone are treated as described in Example 76.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][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]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][N:26](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:25]#[N:26])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C#N)cc2OCC3)n(C(C)C)n1
Temperature: 125 °C
Yield: 59 %

Procedure:
A microwave vial was charged with a solution of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (0.300 mg, 0.699 mmol) in 2.0 ml DMF. To this solution was added zinc cyanide (250 mg, 2.1 mmol). The reaction mixture was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (100 mg, 0.140 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 125° C. for 30 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water×1, saline×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 156 mg of 443 (59% theoretical yield) 1H NMR (400 MHz, DMSO) δ 8.55 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.74-7.46 (m, 2H), 5.79 (dt, J=13.1, 6.6 Hz, 1H), 4.57 (s, 4H), 2.29 (d, J=28.5 Hz, 3H), 1.46 (d, J=6.6 Hz, 6H)
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[CH:3]=1.[CH3:15][N:16]1[CH2:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[CH3:14][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([C:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=3)[N:6]([CH3:7])[N:5]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C)n1-c1cc(Br)n(C)n1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1-c1cc(C2=CCN(C)CC2)n(C)n1
Yield: 67.7 %

Procedure:
Under argon atmosphere, to a mixture of 5-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole (100 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (105 mg), and N,N-dimethylformamide (2 mL) were added a 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride-dichloromethane complex (32 mg), and cesium carbonate (256 mg), followed by reacting them at 80° C. for 1 hour. After leaving to be cooled, ethyl acetate was added thereto, and the mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 4-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazol-5-yl]-1-methyl-1,2,3,6-tetrahydropyridine (72 mg) as a brown oily substance.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16]>C(O)C>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[N:16]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1c(F)cccc1F
Solvent: CCO
Product: O=C(O)C1CCN(c2c(F)cccc2F)C1=O
Yield: 46 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 2,6-difluoroaniline (0.575 g; 4.36 mmol) in ethanol (3 mL). 1-(2,6-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.161 g (46%) was obtained as a solid.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>COCCOCCOC>[OH:5][CH2:6][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccccc1Cc1ccc(C=O)cc1
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: COCCOCCOC
Product: OCc1ccc(Cc2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Sodium borohydride (7.6 g) was added to 200 ml of diglyme, and with stirring at room temperature, a solution of 39.3 g of 4-(2-ethoxycarbonylbenzyl)benzaldehyde in 50 ml of diglyme was added dropwise over the course of 25 minutes. Subsequently, a solution of 9.33 g of anhydrous aluminum chloride in 50 ml of diglyme was added dropwise over the course of 15 minutes. The mixture was stirred at room temperature for 2 hours, and then at 45° to 50° C. for 1 hour. The reaction mixture was poured into about 3 liters of ice water, and stirred. The precipitated crystals were collected by filtration, washed with water, dried, and recrystallized from benzene to afford 28.2 g of 4-(2-hydroxymethylbenzyl)benzyl alcohol as colorless needle-like crystals having a melting point of 101.5° to 102° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.6 %

Procedure:
N-Cbz-L-leucine (Chemical Dynamics) (1.32 g, 4.97 mmol), L-leucine methyl ester hydrochloride (Aldrich) (0.99 g, 5.47 mmol), 1-hydroxybenzotriazole (0.14 g, 1.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.05 g, 5.47 mmol) were combined, dissolved in 25 mL of DMF and stirred at room temperature for 15 h. The solution was diluted with ethyl acetate (250 mL) and washed successively with water, 0.1 N HCl, saturated aqeous NaHCO3 and saturated brine, then dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1:3 ethyl acetate hexanes, to give the title compound as a white solid (1.28 g, 66%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 5H), 6.28 (d, 1H), 5.28 (m, 3H), 4.61-4.58 (m, 1H), 4.20 (m, 1H), 3.74 (s, 3H), 1.69-1.54 (m, 6H), 0.96-0.92 (m, 12H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>>[C:36]([O:35][C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:6]2[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:22][CH:23]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Product: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 65.3 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 0.92 g of ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as described in Preparation 8) and 1.28 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, 1.23 g of the title compound were obtained as crystals, melting at 92°-93° C.